Method of using certain substituted aliphatic secondary amines or their salts for easing breathing

ABSTRACT

Compounds of the formula I 
     
         R.sub.1 --CH(R.sub.2)--N(R.sub.3)--R.sub.4                 (I) 
    
     in which R 1  is unsubstituted or substituted phenyl, R 2  is hydrogen lower alkyl, unsubstituted or substituted phenyl or free or esterified carboxy, and in which R 3  is hydrogen or lower alkyl and R 4  is a group of the formula --alk 1  --X--alk 2  --R 5 , or R 3  and R 4  together are a group of the formula --alk 3  --NH--alk 4  --, alk 1  and alk 2  being lower alkylidene, alk 3  and alk 4  lower alkylene, X a direct bond, methylene or unsubstituted or substituted phenylene and R 5  being hydroxy, amino or substituted amino of the formula --N(R 6 )--CH(R 7 )--R 8  in which R 6  is hydrogen, or, provided that R 3  is hydrogen, it may alternatively be lower alkyl or unsubstituted or substituted phenyl-lower alkyl, R 7  is hydrogen, lower alkyl, unsubstituted or substituted phenyl or free or esterified carboxy and R 8  is unsubstituted or substituted phenyl, and their pharmaceutically acceptable salts have properties that ease breathing and are suitable for combating respiratory disorders, preferably as active ingredients in and/or for the manufacture of pharmaceutical preparations that ease breathing.

The invention relates to the use of compounds of the formula I

    R.sub.1 --CH(R.sub.2)--N(R.sub.3)--R.sub.4                 (I)

in which R₁ is unsubstituted or substituted phenyl, R₂ is hydrogen,lower alkyl, unsubstituted or substituted phenyl or free or esterifiedcarboxy, and in which R₃ is hydrogen or lower alkyl and R₄ is a group ofthe formula --alk₁ --X--alk₂ --R₅, or R₃ and R₄ together are a group ofthe formula --alk₃ --NH--alk₄ --, alk₁ and alk₂ being lower alkylidene,alk₃ and alk₄ lower alkylene, X a direct bond, methylene orunsubstituted or substituted phenylene and R₅ being hydroxy, amino orsubstituted amino of the formula --N(R₆)--CH(R₇)--R₈ in which R₆ ishydrogen, or, provided that R₃ is hydrogen, it may alternatively belower alkyl or unsubstituted or substituted phenyl-lower alkyl, R₇ ishydrogen, lower alkyl, unsubstituted or substituted phenyl or free oresterified carboxy and R₈ is unsubstituted or substituted phenyl, andtheir pharmaceutically acceptable salts for combating respiratorydisorders, for example as the active ingredient in and/or for themanufacture of pharmaceutical preparations that ease breathing, andpharmaceutical preparations that ease breathing and that contain thosecompounds or salts.

As seen from the above proviso definition of alk₁ and alk₂, themethylene group is considered herein to be the lowest member of thealkylidene series as well as of the alkylene series.

The invention also relates to compounds of the formula I in which R₁,R₂, R₃, R₄, R₅, R₆, R₇, R₈, alk₁, alk₂, X, alk₃ and alk₄ have themeanings given above with the proviso, in compounds in which R₃ ishydrogen or lower alkyl, R₄ is a group --alk₁ --X--alk₂ --R₅ and R₅ is agroup --N(R₆)--CH(R₇)--R₈, that, when X is unsubstituted or substitutedphenylene, at least one of the radicals R₁ and R₈ is different fromunsubstituted or N-substituted aminoalkoxyphenyl or at least one of theradicals R₂, R₆ and R₇ is different from hydrogen and lower alkyl, and,when alk₁ and alk₂ are methylene and X is methylene or a direct bond, atleast one of the radicals R₁ and R₈ is different from unsubstitutedphenyl or phenyl mono- or di-substituted by methoxy and/or chlorine orat least one of the radicals R₂, R₃, R₆ and R₇ is different fromhydrogen, and and with the further proviso, in compounds in which R₃ andR₄ together are a group --alk₃ --NH--alk₄ -- and alk₃ is is ethylene,that, when alk₄ is ethylene, R₁ is different from unsubstituted phenylor R₂ is different from unsubstituted phenyl and hydrogen and,furthermore, R₁ is different from 2,3,4-trimethoxyphenyl,o-aminodichlorophenyl, o-acylaminodichlorophenyl ando-diacylaminodichlorophenyl or R₂ is different from hydrogen, and, whenalk₄ is 1,3-propylene, R₁ is different from unsubstituted phenyl or R₂is different from hydrogen, wherein, in the case where R₄ is a group--alk₁ --X--alk₂ --R₅ and alk₁ and alk₂ are methylene and R₅ is a groupof the formula --N(R₆)--CH(R₇)--R₈, R₁ and R₈ are different substituentsselected from phenyl radicals that are unsubstituted or mono-, di-, tri-or tetra-substituted in the 3-, 4-, 5- and/or 6-position(s) byisopropyl, methoxy, hydroxy, chlorine, diethylamino, dimethylaminoand/or nitro when R₂, R₃, R₆ and R₇ are hydrogen and X is methylene, andR₁ and R₈ are different radicals selected from p-aminophenoxyphenyl andp-nitrophenoxyphenyl when R₂ and R₇ are hydrogen and R₃ and R₆ arehydrogen or lower alkyl and X is methylene or a direct bond, and theirpharmaceutically acceptable salts, with the proviso that acid additionsalts with organic carboxylic acids do not have a β-lactam ring in theanion, for use in a process for the therapeutic treatment of the humanor animal body, pharmaceutical preparations containing them and theiruse for combating diseases, or as the active ingredient in or for themanufacture of pharmaceutical preparations.

The invention likewise relates to compounds of a general formula IA,similar to the formula I in which R₁ and R₂ have the meanings givenabove, R₃ is hydrogen or lower alkyl and R₄ is a group of the formula--alk₁ --X--alk₂ --N(R₆)--CH(R₇)--R₈ in which alk₁, X, alk₂, R₆, R₇ andR₈ have the meanings given above, with the proviso that, in compounds ofthe formula IA in which X is unsubstituted or substituted phenylene, atleast one of the radicals R₁ and R₈ is different from unsubstituted orN-substituted aminoalkoxyphenyl when R₂, R₆ and R₇ are hydrogen or loweralkyl, also that, in compounds of the formula IA in which alk₁ and alk₂are methylene and X is methylene or a direct bond, at least one of theradicals R₁ and R₈ is different from unsubstituted phenyl or phenylmono- or di-substituted by methoxy and/or chlorine and fromp-hydroxyphenyl when R₂, R₃, R₆ and R₇ are hydrogen, and with thefurther proviso, in compounds of the formula IA in which alk₁ and alk₂are methylene and X is a direct bond, that, when both radicals R₂ and R₇are hydrogen or both are unsubstituted phenyl or both are methyl or R₂is ethyl and R₇ is hydrogen, at least one of the radicals R₁ and R₈ isdifferent from unsubstituted phenyl or at least one of the radicals R₃and R₆ is different from hydrogen, wherein R₁ and R₈ are differentsubstituents selected from phenyl radicals that are unsubstituted ormono-, di-, tri- or tetra-substituted in the 3-, 4-, 5- and/or6-position(s) by isopropyl, methoxy, hydroxy, chlorine, diethylamino,dimethylamino and/or nitro when R₂, R₃, R₆ and R₇ are hydrogen and X ismethylene, R₁ and R₈ can further be different substituents selected fromp-anilino, p-hydroxyphenyl and p-methylphenyl when R₂, R₃, R₆ and R₇ arehydrogen and X is a direct bond, and R₁ and R₈ are different radicalsselected from p-aminophenoxyphenyl and p-nitrophenoxyphenyl when R₂ andR₇ are hydrogen and R₃ and R₆ are hydrogen or lower alkyl and X ismethylene or a direct bond, and their salts and processes for theirmanufacture.

Phenylene is preferably 1,3- or 1,4-phenylene but may alternatively be1,2-phenylene.

There come into consideration as substituents of phenyl and phenyl inphenyl-lower alkyl and also of phenylene, for example, aliphatic andcycloaliphatic radical, free or etherified or free or esterifiedhydroxy, unsubstituted or substituted amino, nitro and/ortrifluoromethyl.

Esterified carboxy is, for example, aliphatically or cycloaliphaticallyesterified carboxy, such as unsubstituted or substituted loweralkoxycarbonyl or lower alkenyloxy- or lower alkynyloxy-carbonyl or 3-to 8-membered cycloalkoxy-carbonyl.

Aliphatic radicals are, for example, aliphatic hydrocarbon radicals thatare unsubstituted or substituted by hydroxy, lower alkoxy or loweralkanoyloxy, such as lower alkyl, lower alkenyl, lower alkynyl, mono- ordi-hydroxy-lower alkyl, lower alkoxy-lower alkyl or loweralkanoyloxy-lower alkyl.

Cycloaliphatic radicals are, for example, 3- to 8-membered cycloalkylradicals.

Araliphatic radicals are, for example, phenyl-lower alkyl radicals thatare unsubstituted or substituted as indicated for phenyl but arepreferably phenyl-lower alkyl radicals that are unsubstituted orsubstituted by lower alkyl, lower alkoxy, halogen and/ortrifluoromethyl.

Free or etherified or free or esterified hydroxy is, for example,hydroxy etherified by an unsubstituted or substituted aliphatic alcohol,such as lower alkoxy, lower alkenyloxy, lower alkynyloxy, mono- ordi-hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, lower alkanoyl-loweralkoxy or lower alkyl(id)enedioxy bonded to adjacent carbon atoms, orhydroxy esterified by a hydrohalic acid or an organic carboxylic acid,such as halogen, lower alkanoyloxy, or benzoyloxy that is unsubstitutedor substituted as indicated for phenyl, but that is preferablyunsubstituted or substituted by lower alkyl, lower alkoxy, halogenand/or trifluoromethyl.

Unsubstituted or substituted amino is, for example, unsubstituted oraliphatically substituted amino, such as amino, mono- or di-loweralkylamino or lower alkyleneamino, or acylamino, such as mono- ordi-lower alkanoylamino, or benzoylamino that is unsubstituted orsubstituted as indicated for phenyl but that is preferably unsubstitutedor substituted by lower alkyl, lower alkoxy, halogen and/ortrifluoromethyl.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or heptyl.

Lower alkenyl is, for example, vinyl, allyl, methallyl and crotyl.

Phenyl-lower alkyl is, for example, benzyl, 2-phenylethyl, 2- or3-phenylpropyl or triphenylmethyl.

3- to 8-membered cycloalkyl is, for example, cyclopropyl, cyclopentyl,cyclohexyl or cycloheptyl.

Mono- and di-hydroxy-lower alkyl is, for example, 1- or 2-hydroxyethyl,1-, 2- or 3-hydroxypropyl, 1,2-dihydroxyethyl or 1,2-dihydroxypropyl.

Lower alkoxy-lower alkyl is, for example, methoxyethyl, 2-ethoxyethyl,3-methoxypropyl, 3-ethoxypropyl or 1,2-dimethoxyethyl.

Lower alkanoyloxy-lower alkyl is, for example, acetoxymethyl,2-acetoxyethyl or pivaloyloxymethyl.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-, sec-, iso- or tert-butoxy, and pentyloxy, hexyloxy or heptyloxy.

Lower alkenyloxy is, for example, allyloxy or methallyloxy.

Lower alkynyloxy is, for example, propargyloxy.

Mono- or di-hydroxy-lower alkoxy is, for example, hydroxyethoxy, 2- or3-hydroxypropoxy, hydroxyisopropoxy, 2,3-dihydroxypropoxy or1,3-dihydroxy-2-propoxy.

Lower alkoxy-lower alkoxy is, for example, methoxymethoxy,2-methoxyethoxy, 2-ethoxyethoxy or 3-methoxypropoxy.

Lower alkyl(id)enedioxy is, for example, methylenedioxy, ethylenedioxy,1,3-propylenedioxy and isopropylidenedioxy.

Lower alkanoyl-lower alkoxy is, for example, acetylmethoxy, acetylethoxyor pivaloylethoxy.

Lower alkanoyloxy is, for example, acet-, propionyl-, butyryl-,isobutyryl- or pivaloyl-oxy.

Lower alkoxycarbonyl is, for example, methoxycarbonyl, ethoxycarbonyl,n-propoxycarbonyl or tert-butoxycarbonyl.

Lower alkenyloxycarbonyl is, for example, methallyl- orallyloxycarbonyl.

Lower alkynyloxycarbonyl is, for example, propargyloxycarbonyl.

3- to 8-membered cycloalkoxycarbonyl is, for example,cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or cycloheptyloxycarbonyl,also cyclopropoxycarbonyl.

Mono- or di-lower alkylamino is, for example, methylamino, ethylamino,n-butylamino, dimethylamino or diethylamino.

Lower alkyleneamino is, for example, pyrrolidin-1-yl or piperidino.

Mono- or di-lower alkanoylamino is, for example, formylamino,acetylamino, diacetylamino or succinimino.

Halogen is, for example, halogen having an atomic number of up to andincluding 35, such as fluorine, chlorine or bromine.

The compounds of the formula I can form isomers, for example they may bein the form of an optical isomer, for example, depending on the numberof asymmetric carbon atoms, they may be in the form of enantiomers ordiastereoisomers, or in the form of mixtures of the same, for exampleracemates or mixtures of diastereoisomers.

Salts of compounds of the formula I are, for example, thepharmaceutically acceptable acid addition salts thereof, alsopharmaceutically acceptable salts of compounds of the formula I thatcontain carboxy and/or phenolic hydroxy groups, with bases, alsointernal salts of compounds of the formula I that contain carboxy. Acidaddition salts are, for example, pharmaceutically acceptable additionsalts with inorganic acids, such as hydrohalides, for examplehydrochlorides or hydrobromides, bisulphates, phosphates, borates andthe like, also pharmaceutically acceptable addition salts with organicacids, provides that salt-forming organic carboxylic acids do not have aβ-lactam ring, especially acid addition salts with open-chain orcarbocyclic organic acids, such as aliphatic carboxylic acids that arenon-hydroxylated or hydroxylated, such as lower alkane-mono- or-di-carboxylic acid salts, for example acetates, malonates orsuccinates, lower alkene-mono- or -di-carboxylic acid salts, for examplefumarates or maleates, oxo- or hydroxy-lower alkanedicarboxylic acidsalts, such as pyruvates, tartrates, malates and the like, also saltswith organic sulphonic acids, such as aliphatic or aromatic sulphonicacid salts, for example methanesulphonates, benzenesulphonates,p-toluenesulphonates and the like, sulphamates, for exampleN-cyclohexylsulphamates, or salts with 3,7-dihydro-1H-purine-2,6-dionesthat are unsubstituted or 1-, 3- and/or 8-substituted, for example with8-chloro-3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione. Pharmaceuticallyacceptable base salts are, for example, alkali metal or alkaline earthmetal salts, for example sodium, potassium, magnesium or calcium salts,and, in the case of compounds of the formula I containing carboxy, alsoammonium salts with ammonia or organic amines, such as mono-, di- andtri-lower alkylamines, for example ethyl-, diethyl- or trimethyl-amine,or mono-, di- and tri-(hydroxy-lower alkyl)-amines, for exampleethanolamine or di- or tri-ethanolamine.

Some of the compounds of the formula I are known and are proposedpredominantly as intermediates for the manufacture of fine chemicalshaving various uses. Some, however, are also known to havepharmacological properties on the basis of which they can be used as theactive ingredient of medicaments, for example in antihistamines,spasmolysants, antiarrythmic agents and antidepressants. According toGerman Offenlegungsschrift No. 2 551 355, a narrowly defined group ofcompounds of the formula I, namely those in which R₁ is phenylsubstituted in the o-position by amino, mono- or di-acylamino andadditionally by 2 chlorine atoms, R₂ is hydrogen and R₃ and R₄ togetherare a group of the formula --CH₂ CH₂ NHCH₂ CH₂ --, possess, in addition,properties that stimulate the fluid secretion of the respiratory tractand they have been proposed, inter alia, as expectorants.

The invention is based on the surprising discovery that the compounds ofthe formula I and their pharmaceutically acceptable salts haveproperties that ease breathing to a marked extent. Thus, they increaserespiratory capacity without generally significantly increasingrespiratory frequency. In this respect, the compounds of the formula Idiffer essentially from the so-called respiratory stimulants, such as,N,N-diethylpyridine-3-carboxamide (nikethamide) and the combination(prethcamide) of N-ethyl-N-(1-dimethylcarbamoylpropyl)-crotonamide(crotethamide) and N-propyl-N-(1-dimethylcarbamoylpropyl)-crotonamide(cropropamide), the effect of which on respiratory capacity consistsespecially in an increase in respiratory frequency. Onlyα-phenyl-α-(2-piperidinyl)-methyl acetate (methyl phenidate) is known tohave a similar action. This compound, however, like the above-mentionedrespiratory stimulants, belongs to a completely different class ofsubstances. It also has pronounced, and not in all cases desirable,effects of stimulating the central nervous system and also undesirableproperties.

The properties of easing breathing possessed by the compounds of theformula I and their salts can be demonstrated in tests on animals, forexample the test arrangement according to Agents and Actions 3, 28-34(1973).

According to this arrangement, both male and female rabbits weighingfrom 2 to 3 kg are narcotised with ethylurethane (1.2 g/kg s.c.) andbound in the supine position and a tracheotomy tube is introduced. Therespiratory activity is recorded on the basis of the pleural pressure(P_(pl)). The trachea is closed every 20 minutes and kept closed for 30seconds. The first closure of the trachea gives the normal individualrespiratory capacity value. 3 minutes before each subsequent closure ofthe trachea, an aqueous solution of the test substance is administeredintravenously in the course of 60 seconds. After each measurement thedose is increased by a factor of 3, the starting dose being such thatthe lethal dose (D₁) is reached at approximately the 7th administration.To establish actual effectiveness, for the entire period during whichthe trachea is closed the average pleural negative pressure duringinspiration and expiration, including the following pause (p_(i)), themaximum pleural negative pressure developed during attempts to breathein (p_(i) ^(max)) and the respiratory frequency (f_(r)) are measured foreach breath. All three parameters are then averaged out over the entireperiod during which the trachea is closed. The increasing effect of thetest substance on respiratory capacity is demonstrated in an increase inthe average pleural negative pressure (Δp_(i)) and in the maximumpleural negative pressure (Δp_(i) ^(max)) compared with the normal valuewhich is set at 100%.

In this test, the values listed in the following Table were establishedfor the increase obtainable in the average and maximum pleural negativepressures (Δp_(i)) and (Δp_(i) ^(max)), respectively, and the change inrespiratory frequency (Δf_(r)) and also for the minimum dose at whichthe p_(i) significantly increases (D_(e) in g/kg) and the lethal dose(D₁ in g/kg):

    ______________________________________                                        Test substance                                                                            Δ-p.sub.i                                                                      Δ p.sub.i.sup.max                                                               Δ f.sub.r                                                                     D.sub.e                                                                             D.sub.1                                ______________________________________                                        I*.sup.a     4%    14%     +5%   0.003 over 0.01                              II*.sup.a   10%    0%      0%    0.002 over 0.04                              III*.sup.a  17%    3%      +2%   0.0005                                                                              0.01                                   IV*.sup.a   20%    27%     +5%   0.0002                                                                              0.002                                  V*.sup.a    13%    21%     +2%   0.001 0.04                                   VI*.sup.a   7%     11%     +1%   0.002 over 0.01                              VII*.sup.a  13%    23%     +1%   0.003 0.1                                    VIII*.sup.a 13%    10%     +3%   0.001 0.03                                   IX*.sup.a   18%    16%     +3%   0.002 0.03                                   X*.sup.a    14%    28%     -9%   0.001 0.01                                   XI*.sup.a   11%    9%      -3%   0.005 over 0.01                              XII*.sup.a  9%     2%      +7%   0.001 0.03                                   XIII*.sup.a 18%    19%     +1%   0.002 0.03                                   XIV*.sup.b  29%    12%     +2%   0.002 0.04                                   XV*.sup.a   9%     11%     0     0.003 over 0.01                              XVI*.sup.a  15%    5%      +15%  0.015 over 0.04                              XVII*.sup.a 20%    20%     +5%   0.002 over 0.01                              XVIII.sup.a 12%    4%      + 11% 0.003 0.03                                   XIX*.sup.a  25%    17%     +9%   0.002 0.02                                   methyl      17%    9%      -1%   0.003 0.05                                   phenidate.sup.c                                                               nikethamide 19%    12%     +84%  0.1   0.3                                    prethcamide  5%    2%      +15%  0.1   over 0.1                               strychnine   2%    6%      -4%   0.0001                                                                              0.003                                  ______________________________________                                         .sup.a = administered as bismethanesulphonate,                                .sup.b = administered as methanesulphonate,                                   .sup.c = administered as hydrochloride.                                  

The effect of the compounds of the formula I of easing breathing wasconfirmed in human beings in a preliminary clinical trial using aselected compound. For example, with 4 test persons the followingobservations were made after administeringN,N'-bis-(diphenylmethyl)-1,2-propylenediamine (V*,).

Test person 1: (male, age 73, pulmonary emphysema) was given p.o. 10 mgof active ingredient. 1 hour later the vital capacity (VC) and theforced expiratory volume at 1 second (FEV₁,0) were 3.3 l and 2.7 lcompared with 2.5 l and 2.1 l as the starting values. No side effectswere observed.

Test person 2: (male, age 77, pulmonary emphysema and pulmonary heartdisease) was given i.v. 10 mg of active ingredient in the form of anaqueous solution of bis-methanesulphonate. 1 hour later the vitalcapacity (VC) and the forced expiratory volume at 1 second (FEV₁,0) were2.5 l and 2.4 l compared with 2.1 l and 2.0 l as the starting values. Noside effects were observed.

Test person 3: (male, age 72, pulmonary emphysema) suffering fromdyspnea was given, p.o. in a placebo test, a placebo and 10 mg of activeingredient. 2 hours after the administration of the placebo the vitalcapacity (VC) and the forced expiratory volume at 1 second (FEV₁,0) were2.1 l and 1.3 l compared with 2.1 l and 1.2 l as the starting values;the subjective condition was unchanged. 2 hours after the administrationof the active ingredient, the vital capacity (VC) and the forcedexpiratory volume at 1 second (FEV₁,0) were 2.6 l and 1.25 l comparedwith 2.2 l and 1.2 l and the test person stated that he could breathe"more easily" and felt stronger.

Test person 4: (male, age 84, pulmonary emphysema) suffering fromdyspnea was given 10 mg of active ingredient and a placebo in a placebotest. 2 hours after the administration of the active ingredient thevital capacity (VC) and the forced expiratory volume at 1 second(FEV₁,0) were 1.85 l and 1.0 l compared with 1.6 l and 0.7 l. The testperson stated that he could breathe "more easily and freely". 2 hoursafter the administration of the placebo the vital capacity (VC) and theforced expiratory volume at 1 second (FEV₁,0) were 1.65 l and 0.75 lcompared with 1.6 l and 0.7 l, and the subjective condition wasunchanged.

Because of their specific action of increasing respiratory capacity, thecompounds of the formula I are accordingly suitable as the activeingredients of medicaments in pharmaceutical preparations that easebreathing, for the prophylactic and therapeutic influencing ofrespiratory disorders of the most varied origins, especially respiratorydisorders caused by old age. They may, however, also be used for thecontrolled increase of respiratory capacity, for example in the case ofunfavourable respiratory conditions.

The invention relates especially to the use of compounds of the formulaIC

    R.sub.1 --CH(R.sub.2)--N(R.sub.3)--R.sub.4                 (IC)

in which R₁ is unsubstituted phenyl or phenyl substituted by aliphatic,cycloaliphatic or araliphatic radicals, by hydroxy, etherified oresterified hydroxy, unsubstituted or aliphatically substituted amino,acylamino, nitro and/or by trifluoromethyl, R₂ is hydrogen, lower alkyl,unsubstituted phenyl or phenyl substituted by aliphatic, cycloaliphaticor araliphatic radicals, by hydroxy, etherified or esterified hydroxy,unsubstituted or aliphatically substituted amino, acylamino, nitroand/or by trifluoromethyl, or is aliphatically, cycloaliphatically oraraliphatically esterified carboxy, and in which R₃ is hydrogen or loweralkyl and R₄ is a group of the formula --alk₁ --X--alk₂ --R₅ or R₃ andR₄ together are a group of the formula --alk₃ --NH--alk₄ --, whereinalk₁ and alk₂ are lower alkylidene, alk₃ and alk₄ are lower alkylene, Xis a direct bond, methylene or unsubstituted phenylene or phenylenesubstituted by aliphatic, cycloaliphatic or araliphatic radicals, byhydroxy, etherified or esterified hydroxy, unsubstituted oraliphatically substituted amino, acylamino, nitro and/or bytrifluoromethyl, R₅ is hydroxy, amino or substituted amino of theformula --N(R₆)--CH(R₇)--R₈ in which R₆ is hydrogen or, provided that R₃is hydrogen, it may alternatively be lower alkyl or unsubstitutedphenyl-lower alkyl or phenyl-lower alkyl substituted by aliphatic,cycloaliphatic or araliphatic radicals, by hydroxy, etherified oresterified hydroxy, unsubstituted or aliphatically substituted amino,acylamino, nitro and/or by trifluoromethyl, R₇ is hydrogen, lower alkyl,unsubstituted phenyl or phenyl substituted by aliphatic, cycloaliphaticor araliphatic radicals, by hydroxy, etherified or esterified hydroxy,unsubstituted or aliphatically substituted amino, acylamino, nitroand/or by trifluoromethyl or is aliphatically, cycloaliphatically oraraliphatically esterified carboxy, and R₈ is unsubstituted phenyl orphenyl substituted by aliphatic, cycloaliphatic or araliphatic radicals,by hydroxy, etherified or esterified hydroxy, unsubstituted oraliphatically substituted amino, acylamino, nitro and/or bytrifluoromethyl, and their pharmaceutically acceptable salts forcombating respiratory disorders, for example as the active ingredient inand/or for the manufacture of pharmaceutical preparations that easebreathing and also pharmaceutical preparations that ease breathing andthat contain those compounds or salts.

The invention also relates especially to compounds of the formula I inwhich R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, alky₁, alk₂, X, alk₃ and alk₄ havethe meanings given above with the proviso, in compounds in which R₃ ishydrogen or lower alkyl, R₄ is a group --alk₁ --X--alk₂ --R₅ and R₅ is agroup --N(R₆)--CH(R₇)--R₈, that, when X is unsubstituted phenylene orphenylene substituted as indicated, at least one of the radicals R₁ andR₈ is different from unsubstituted or N-substituted aminoalkoxyphenyl orat least one of the radicals R₂, R₃, R₆ and R₇ is different fromhydrogen or lower alkyl, and that, when alk₁ and alk₂ are methylene andX is methylene or a direct bond, at least one of the radicals R₁ and R₈is different from unsubstituted phenyl or phenyl mono- or di-substitutedby methoxy and/or chlorine or at least one of the radicals R₂, R₃, R₆and R₇ is different from hydrogen, and with the further proviso, incompounds in which R₃ and R₄ together are a group --alk₃ --NH--alk₄ --and alk₃ is ethylene, that, when alk₄ is ethylene, R₁ is different fromunsubstituted phenyl or R₂ is different from unsubstituted phenyl andhydrogen and also R₁ is different from 2,3,4-trimethoxyphenyl,o-aminodichlorophenyl, o-acylaminodichlorophenyl ando-diacylaminodichlorophenyl or R₂ is different from hydrogen, and that,when alk₄ is 1,3-propylene, R₁ is different from unsubstituted phenyl orR₂ is different from hydrogen, wherein, in the case where R₄ is a group--alk₁ --X--alk₂ --R₅ and alk₁ and alk₂ are methylene and R₅ is a groupof the formula --N(R₆)--CH(R₇)--R₈, R₁ and R₈ are different substituentsselected from phenyl radicals that are unsubstituted or mono-, di-, tri-or tetra-substituted in the 3, 4-, 5- and/or 6-position(s) by isopropyl,methoxy, hydroxy, chlorine, diethylamino and/or dimethylamino when R₂,R₃, R₆ and R₇ are hydrogen and X is methylene, and R₁ and R₈ aredifferent radicals selected from p-aminophenoxyphenyl andp-nitrophenoxyphenyl when R₂ and R₇ are hydrogen and R₃ and R₆ arehydrogen or lower alkyl and X is methylene or a direct bond, and theirpharmaceutically acceptable salts, with the proviso that acid additionsalts with organic carboxylic acids do not have a β-lactam ring in theanion, for use in a method for the therapeutic treatment of the human oranimal body, pharmaceutical preparations containing them and their usefor combating diseases or as the active ingredient in or for themanufacture of pharmaceutical preparations.

The invention likewise relates especially to compounds of the formula 1in which R₁ and R₂ have the meanings given above, R₃ is hydrogen orlower alkyl and R₄ is a group of the formula --alk₁ --X--alk₂--N(R₆)--CH(R₇)--R₈ in which alk₁, X, alk₂, R₆, R₇ and R₈ have themeanings given above, with the proviso that, in compounds of the formulaI in which X is unsubstituted phenylene or phenylene substituted asindicated, at least one of the radicals R₁ and R₈ is different fromunsubstituted or N-substituted aminoalkoxyphenyl when R₂, R₃, R₆ and R₇are hydrogen or lower alkyl, further that, in compounds in which alk₁and alk₂ are methylene and X is methylene or a direct bond, at least oneof the radicals R₁ and R₈ is different from unsubstituted phenyl orphenyl mono- or di-substituted by methoxy and/or chlorine and fromp-hydroxyphenyl, when R₂, R₃, R₆ and R₇ are hydrogen, and with thefurther proviso, in compounds in which alk₁ and alk₂ are methylene and Xis a direct bond, that, when both radicals R₂ and R₇ are hydrogen, orboth are unsubstituted phenyl or both are methyl or R₂ is ethyl and R₇is hydrogen, at least one of the radicals R₁ and R₈ is different fromunsubstituted phenyl or at least one of the radicals R₃ and R₆ isdifferent from hydrogen, wherein R₁ and R₈ are different substituentsselected from phenyl radicals that are unsubstituted or mono-, di-, tri-or tetra-substituted in the 3-, 4-, 5- and/or 6-position(s) byisopropyl, methoxy, hydroxy, chlorine, diethylamino and/or dimethylaminoor are mono- or disubstituted in the 4- and/or 6-position by chlorineand/or nitro when R₂, R₃, R₆ and R₇ are hydrogen and X is methylene, R₁and R.sub. 8 are different substituents selected from p-anilino,p-hydroxyphenyl and p-methylphenyl when R₂, R₃, R₆ and R₇ are hydrogenand X is a direct bond, and R₁ and R₈ are different radicals selectedfrom p-aminophenoxyphenyl and p-nitrophenoxyphenyl when R₂ and R₇ arehydrogen and R₃ and R₆ are hydrogen or lower alkyl and X is methylene ora direct bond, and their salts, preferably pharmaceutically acceptableacid addition salts, and processes for their manufacture.

The invention relates more especially to the use of compounds of theformula I in which R₁ is unsubstituted phenyl or phenyl substituted bylower alkyl, such as methyl, lower alkenyl, such as vinyl or allyl,lower alkynyl, such as propargyl, mono- or di-hydroxy-lower alkyl, suchas hydroxymethyl or 2-hydroxyethyl, lower alkoxy-lower alkyl, such asethoxymethyl, lower alkanoyloxy-lower alkyl, such as acetoxymethyl or2-acetoxyethyl, 3- to 8-membered cycloalkyl, such as cyclohexyl,hydroxy, lower alkoxy, such as methoxy, lower alkenyloxy, such asallyloxy, lower alkynyloxy, such as propargyloxy, mono- ordi-hydroxy-lower alkoxy, such as 2-hydroxyethoxy, lower alkoxy-loweralkoxy, such as 2-methoxyethoxy, lower alkyl(id)enedioxy bonded toadjacent carbon atoms, such as ethylenedioxy or 2,2-propylenedioxy,halogen having an atomic number of up to and including 35, such aschlorine, lower alkanoyloxy, such as acetoxy, amino, mono- or di-loweralkylamino, such as methyl- or dimethyl-amino, and/or by mono- ordi-lower alkanoylamino, such as acetylamino or diacetylamino, R₂ ishydrogen, lower alkyl, unsubstituted phenyl or phenyl substituted asindicated for R₁, lower alkoxycarbonyl, such as methoxy- orethoxy-carbonyl, or 3- to 8-membered cycloalkoxycarbonyl, such ascyclohexyloxycarbonyl, R₃ is hydrogen, lower alkyl or phenyl-loweralkyl, such as methyl, and R₄ is a group of the formula --alk₁ --X--alk₂--R₅, or R₃ and R₄ together are a group of the formula --alk₃ --NH--alk₄--, wherein alk₁ and alk₂ are lower alkylidene, such as methylene, alk₃and alk₄ are lower alkylene, such as ethylene or 1,3-propylene, X ismethylene, a direct bond or unsubstituted phenylene or phenylenesubstituted by lower alkyl, such as methyl, lower alkoxy, such asmethoxy, halogen and/or by trifluoromethyl, R₅ is hydroxy, amino orsubstituted amino of the formula --N(R₆)--CH(R₇)--R₈, R₆ is hydrogen or,provided that R₃ is hydrogen, may alternatively be lower alkyl, such asmethyl, R₇ is hydrogen, lower alkyl, such as methyl, or unsubstitutedphenyl or phenyl substituted as indicated for R₂, lower alkoxycarbonyl,such as methoxy- or ethoxycarbonyl, or 3- to 8-memberedcycloalkoxycarbonyl, such as cyclohexyloxycarbonyl, and R₈ isunsubstituted phenyl or phenyl substituted as indicated for R₁, andtheir pharmaceutically acceptable acid addition salts or base salts forcombating respiratory disorders, for example as the active ingredient inor for the manufacture of medicaments that ease breathing, and alsopreparations that ease breathing and that contain those compounds orsalts.

The invention also relates more especially to compounds of the formula Iin which R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, alk₁, X, alk₂, alk₃ and alk₄have the meanings given above with the proviso, in compounds of theformula I in which R₃ and R₄ together are a group --alk₃ --NH--alk₄ --and alk₃ is ethylene, that, when alk₄ is ethylene, R₁ is different fromunsubstituted phenyl or R₂ is different from unsubstituted phenyl andhydrogen and also R₁ is different from 2,3,4-trimethoxyphenyl,o-aminodichlorophenyl, o-lower alkanoylaminodichlorophenyl ando-di-lower alkanoylaminodichlorophenyl or R₂ is different from hydrogen,and, when alk₄ is 1,3-propylene, R₁ is different from unsubstitutedphenyl or R₂ is different from hydrogen, and with the further proviso,in compounds of the formula I in which R₄ is a group --alk₁ --X--alk₂--R₅ and R₅ is a group --N(R₆)--CH(R₇)--R₈, that, when alk₁ and alk₂ aremethylene and X is methylene or a direct bond, at least one of theradicals R₁ and R₈ is different from unsubstituted phenyl or phenylmono- or di-substituted by methoxy and/or chlorine or at least one ofthe radicals R₂, R₃, R₆ and R₇ is different from hydrogen, wherein, inthe case where R₄ is a group --alk₁ --X--alk₂ --R₅ and alk₁ and alk₂ aremethylene and R₅ is a group of the formula --N(R₆)--CH(R₇)--R₈, R₁ andR₈ are different substituents selected from phenyl radicals that areunsubstituted or mono-, di-, tri- or tetra-substituted in the 3-, 4-, 5-and/or 6-position(s) by isopropyl, methoxy, hydroxy, chlorine,diethylamino and/or dimethylamino when R₂, R₃, R₆ and R₇ are hydrogenand X is methylene, or their pharmaceutically acceptable acid additionsalts, with the proviso that addition salts with organic carboxylicacids do not have a β-lactam ring, for use in a method for thetherapeutic treatment of the human or animal body, their use forcombating diseases or for the manufacture of medicaments and alsopharmaceutical preparations containing those salts or compounds.

The invention likewise relates more especially to compounds of theformula I in which R₁ and R₂ have the meanings given above, R₃ ishydrogen or lower alkyl, such as methyl, and R₄ is a group of theformula --alk₁ --X--alk₂ --N(R₆)--CH(R₇)--R₈ in which alk₁, X, alk₂, R₆,R₇ and R₈ have the meanings given above, with the proviso that, incompounds of the formula I in which alk₁ and alk₂ are methylene and X ismethylene or a direct bond, at least one of the radicals R₁ and R₈ isdifferent from unsubstituted phenyl or phenyl mono- or di-substituted bymethoxy and/or chlorine and from p-hydroxyphenyl when R₂, R₃, R₆ and R₇are hydrogen, and with the further proviso, in compounds of the formulaI in which alk₁ and alk₂ are methylene and X is a direct bond, that,when both radicals R₂ and R₇ are hydrogen or both are methyl or both areunsubstituted phenyl or R₂ is ethyl and R₇ is hydrogen, at least one ofthe radicals R₁ and R₈ is different from unsubstituted phenyl or atleast one of the radicals R₃ and R₆ is different from hydrogen, whereinR₁ and R₈ are different substituents selected from phenyl radicals thatare unsubstituted or mono-, di-, tri- or tetra-substituted in the 3-,4-, 5- and/or 6-position(s) by isopropyl, methoxy, hydroxy, chlorine,diethylamino and/or dimethylamino when R₂, R₃, R₆ and R₇ are hydrogenand X is methylene, and R₁ and R₈ are different substituents selectedfrom p-anilino, p-hydroxyphenyl and p-methylphenyl when R₂, R₃, R₆ andR₇ are hydrogen and X is a direct bond, and their acid addition saltsand processes for their manufacture.

The invention relates especially to the use of compounds of the formulaI in which R₁ is unsubstituted phenyl or phenyl substituted by loweralkyl, such as methyl, lower alkenyl, such as allyl, 3- to 8-memberedcycloalkyl, such as cyclohexyl, lower alkoxy, such as methoxy, loweralkenyloxy, such as allyloxy, lower alkylenedioxy bonded to adjacentcarbon atoms, such as ethylenedioxy or 2,2-propylenedioxy, halogenhaving an atomic number of up to and including 35, such as chlorine,amino and/or by mono- or di-lower alkylamino, such as methyl- ordiethyl-amino, R₂ is hydrogen or unsubstituted phenyl or phenylsubstituted as indicated for R₁, R₃ is hydrogen or lower alkyl, such asmethyl, and R₄ is a group of the formula --alk₁ --X--alk₂ --R₅ or R₃ andR₄ together are a group of the formula --alk₃ --NH--alk₄ --, whereinalk₁ and alk₂ are lower alkylidene, such as methylene, alk₃ and alk₄ arelower alkylene, such as ethylene or 1,3-propylene, X is a direct bond,methylene or unsubstituted phenylene, R₅ is a group --N(R₆)--CH(R₇)--R₈,R₆ is hydrogen or, provided that R₃ is hydrogen, may alternatively belower alkyl, such as methyl, R₇ is hydrogen, lower alkyl, such asmethyl, unsubstituted phenyl or phenyl substituted as indicated for R₁,lower alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, or 3- to8-membered cycloalkoxycarbonyl, such as cyclohexyloxycarbonyl, and R₈ isunsubstituted phenyl or phenyl substituted as indicated for R₁, andtheir pharmaceutically acceptable acid addition salts for combatingrespiratory disorders, for example as the active ingredient in or forthe manufacture of medicaments that ease breathing, and alsopreparations that ease breathing and that contain those compounds orsalts.

The invention also relates especially to compounds of the formula I inwhich R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, alk₁, X, alk₂, alk₃ and alk₄ havethe meanings given above with the proviso, in compounds of the formula Iin which R₃ and R₄ together are a group --alk₃ --NH--alk₄ -- and alk₃ isethylene, that, when alk₄ is ethylene, R₁ is different fromunsubstituted phenyl or R₂ is different from unsubstituted phenyl andhydrogen and also R₁ is different from 2,3,4-trimethoxyphenyl ando-aminodichlorophenyl or R₂ is different from hydrogen, and that, whenalk₄ is 1,3-propylene, R₁ is different from unsubstituted phenyl or R₂is different from hydrogen, and with the further proviso, in compoundsof the formula I in which R₄ is a group --alk₁ --X--alk₂ --R₅ and R.sub.5 is a group --N(R₆)--CH(R₈)--R₇, that, when alk₁ and alk₂ are methyleneand X is methylene or a direct bond, at least one of the radicals R₁ andR₈ is different from unsubstituted phenyl or phenyl mono- ordi-substituted by methoxy and/or chlorine or at least one of theradicals R₂, R₃, R₆ and R₇ is different from hydrogen, wherein, in thecase where R₄ is a group --alk₁ --X--alk₂ --R₅ and alk₁ and alk₂ aremethylene and R₅ is a group of the formula --N(R₆)--CH(R₇)--R₈, R₁ andR₈ are different substituents selected from phenyl radicals that areunsubstituted or mono-, di-, tri- or tetra-substituted in the 3-, 4-, 5-and/or 6-position(s) by isopropyl, methoxy, chlorine, diethylaminoand/or dimethylamino when R₂, R₃, R₆ and R₇ are hydrogen and X ismethylene, or their pharmaceutically acceptable acid addition salts,with the proviso that addition salts with organic carboxylic acids donot have a β-lactam ring, for use in a method for the therapeutictreatment of the human or animal body, their use for combating diseasesor for the manufacture of medicaments and also pharmaceuticalpreparations containing those compounds or salts.

The invention likewise relates especially to compounds of the formula Iin which R₁ and R₂ have the meanings given above, R₃ is hydrogen orlower alkyl, such as methyl, and R₄ is a group of the formula --alk₁--X--alk₂ --N(R₆)--CH(R₇)--R₈ in which alk₁, X, alk₂, R₆, R₇ and R₈ havethe meanings given above, with the proviso that, in compounds of theformula I in which alk₁ and alk₂ are methylene and X is methylene or adirect bond, at least one of the radicals R₁ and R₈ is different fromunsubstituted phenyl or phenyl mono- or di-substituted by methoxy and/orchlorine when R₂, R₃, R₆ and R₇ are hydrogen, and with the furtherproviso, in compounds of the formula I in which alk₁ and alk₂ aremethylene and X is a direct bond, that, when both radicals R₂ and R₇ arehydrogen or both are unsubstituted phenyl at least one of the radicalsR₁ and R₈ is different from unsubstituted phenyl or at least one of theradicals R₃ and R₆ is different from hydrogen, wherein R₁ and R₈ aredifferent substituents selected from phenyl radicals that areunsubstituted or mono-, di-, tri- or tetra-substituted in the 3-, 4-, 5-and/or 6-position(s) by isopropyl, methoxy, chlorine, diethylaminoand/or dimethylamino when R₂, R₃, R₆ and R₇ are hydrogen and X ismethylene, and R₁ and R₈ are different radicals selected from p-anilinoand p-methylphenyl when R₂, R₃, R₆ and R₇ are hydrogen and X is a directbond, and their acid addition salts and also processes for theirmanufacture.

The invention relates most especially to the use of compounds of theformula I in which R₁ is unsubstituted phenyl or phenyl substituted bylower alkyl having up to and including 4 carbon atoms, such as methyl,and/or by halogen having an atomic number of up to and including 35,such as chlorine, R₂ is hydrogen or unsubstituted phenyl or phenylsubstituted as indicated for R₁, R₃ is hydrogen or lower alkyl having upto and including 4 carbon atoms, such as methyl, and R₄ is a group ofthe formula --CH₂ --X--CH₂ --R₅ or R₃ and R₄ together are a group of theformula --alk₃ --NH--CH₂ CH₂ --, in which X is a direct bond, methyleneor unsubstituted phenylene, R₅ is amino or substituted amino of theformula --N(R₆)--CH(R₇)--R₈, R₆ is hydrogen or, provided that R₃ ishydrogen, it may alternatively be lower alkyl having up to and including4 carbon atoms, such as methyl, R₇ is hydrogen, lower alkyl having up toand including 4 carbon atoms, such as methyl, unsubstituted phenyl orphenyl substituted as indicated for R₁ or lower alkoxycarbonyl having upto and including 4 carbon atoms in the alkyl moiety, such asmethoxycarbonyl, R₈ is unsubstituted phenyl or phenyl substituted asindicated for R₁, and alk₃ is lower alkylene having from 2 to 4 carbonatoms which separates the two nitrogen atoms by 2 or 3 carbon atoms,such as methylene, ethylene or 1,3-propylene, and their pharmaceuticallyacceptable acid addition salts for combating respiratory disorders, forexample as the active ingredient in or for the manufacture ofpharmaceutical preparations, and also medicaments that ease breathingand that contain those compounds or salts.

The invention also relates most especially to compounds of the formula Iin which R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, X and alk₃ have the meaningsgiven above with the proviso, in compounds in which R₃ is hydrogen orlower alkyl having up to and including 4 carbon atoms and R₄ is a groupof the formula --CH₂ --X--CH₂ --N(R₆)--CH(R₇)--R₈, that, when X ismethylene or a direct bond, at least one of the radicals R₁ and R₈ isdifferent from unsubstituted phenyl or phenyl mono- or di-substituted bychlorine or at least one of the radicals R₂, R₃, R₆ and R₇ is differentfrom hydrogen, and with the further proviso, in compounds in which R₃and R₄ together are a group --alk₃ --NH--CH₂ CH₂ --, that, when alk₃ isethylene, R₁ is different from unsubstituted phenyl or R₂ is differentfrom unsubstituted phenyl and hydrogen, and, when alk₄ is 1,3-propylene,R₁ is different from unsubstituted phenyl or R₂ is different fromhydrogen, wherein R₁ and R₈ are different substituents selected fromphenyl that is unsubstituted or mono-, di-, tri- or tetra-substituted inthe 3-, 4-, 5- and/or 6-position(s) by isopropyl and/or chlorine whenR₂, R₃, R₆ and R₇ are hydrogen and X is methylene, or theirpharmaceutically acceptable acid addition salts, with the proviso thataddition salts with organic carboxylic acids do not have a β-lactamring, for use in a method for the therapeutic treatment of the human oranimal body, their use for combating diseases or for the manufacture ofmedicaments and also pharmaceutical preparations containing thosecompounds or salts.

The invention likewise relates most especially to compounds of theformula I in which R₁ and R₂ have the meanings given above, R₃ ishydrogen or lower alkyl having up to and including 4 carbon atoms, suchas methyl, and R₄ is a group of the formula --CH₂ --X--CH₂--N(R₆)--CH(R₇)--R₈, wherein X, R₆, R₇ and R₈ have the meanings givenabove, with the proviso that, when X is methylene or a direct bond, atleast one of the radicals R₁ and R₈ is different from unsubstitutedphenyl or phenyl mono- or di-substituted by chlorine or at least one ofthe radicals R₂, R₃, R₆ and R₇ is different from hydrogen, and with thefurther proviso that, when both radicals R₂ and R₇ are hydrogen or bothare unsubstituted phenyl and X is a direct bond, at least one of theradicals R₁ and R₈ is different from unsubstituted phenyl or at leastone of the radicals R₃ and R₆ is different from hydrogen, and, when R₂,R₃, R₆ and R₇ are hydrogen and X is methylene, at least one of theradicals R₁ and R₈ is different from p-methylphenyl, wherein R₁ and R₈are different substituents selected from phenyl that is unsubstituted ormono-, di-, tri- or tetra-substituted in the 3-, 4-, 5- and/or6-position(s) by isopropyl and/or chlorine when R₂, R₃, R₆ and R₇ arehydrogen and X is methylene, and their acid addition salts, especiallypharmaceutically acceptable acid addition salts, and also processes fortheir manufacture.

The invention relates especially to

N,N'-bis-(diphenylmethyl)-1,3-propylenediamine (I*),

N,N'-bis-(diphenylmethyl)-p-xylylenediamine (II*),

N-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine (III*),

N-diphenylmethyl-N'-(α-methoxycarbonylbenzyl)-ethylenediamine (IV*),

N,N'-bis-(diphenylmethyl)-1,2-propylenediamine (V*),

N,N'-bis-(diphenylmethyl)-m-xylylenediamine (VI*),

N,N-dibenzyl-N'-diphenylmethyl-ethylenediamine (VII*),

N,N'-di-(o-methylbenzyl)-ethylenediamine (VIII*) and

N,N'-dibenzyl-N-methyl-ethylenediamine (IX*)

and also their salts, especially their pharmaceutically acceptable acidaddition salts, especially for use in a method for the therapeutictreatment of the human or animal body, processes for their manufacture,their use as the active ingredients in medicaments or for themanufacture of medicaments, and pharmaceutical preparations containingthem, also the use of

N,N'-bis-(diphenylmethyl)-ethylenediamine (X*),

N-diphenylmethyl-ethylenediamine (XI*),

N,N'-di-(p-methylbenzyl)-ethylenediamine (XII*)

and also their pharmaceutically acceptable acid addition salts, with theproviso that addition salts with organic carboxylic acids do not have aβ-lactam ring in the anion, for combating diseases, for example for usein a method for the therapeutic treatment of the human or animal body,for example as the active ingredients in medicaments, also the use of

1-diphenylmethyl-piperazine (XIII*),

2-diphenylmethylamino-ethanol (XIV*),

N,N'-dibenzyl-ethylenediamine (XV*),

1-benzyl-piperazine (XVI*),

N,N'-di-(p-chlorobenzyl)-ethylenediamine (XVII*),

N,N'-di-(3,4-dichlorobenzyl)-ethylenediamine (XVIII*),

N,N'-di-(1-phenylethyl)-ethylenediamine (XIX*)

and their pharmaceutically acceptable acid addition salts for combatingrespiratory disorders, for example as active ingredients in or for themanufacture of medicaments that ease breathing, and also pharmaceuticalpreparations that ease breathing and that contain those compounds orsalts.

The compounds of the formula I can be manufactured according to methodsknown per se. Thus, novel compounds of the formula I in which R₄ is agroup of the formula --alk₁ --X--alk₂ --N(R₆)--CH(R₇)--R₈ are obtained,for example, by condensing a compound of the formula

    Y.sub.1 --alk.sub.1 --X--alk.sub.2 --N(R.sub.6)--CH(R.sub.7)--R.sub.8 (II)

with a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III)

one of the radicals Y₁ and Y₂ being a nucleophilically replaceable groupY and the other being a group of the formula --N(R₃)--H, if necessaryseparating an isomeric mixture obtainable according to the process intoits components and, if desired, converting a compound obtainableaccording to the process into a different compound of the formula Iand/or converting a compound obtainable according to the process into asalt or converting a salt obtainable according to the process into thefree compound or into a different salt.

Nucleophilically replaceable groups Y are, for example, reactivelyesterified hydroxy groups, such as hydroxy groups esterified by aninorganic acid or by an organic sulphonic acid, also ammonium andsulphonium groups. Hydroxy esterified by an inorganic acid is, forexample, hydroxy esterified by a hydrohalic acid, for examplehydrochloric, hydrobromic or hydriodic acid, and alsofluorosulphonyloxy. Hydroxy esterified by an organic sulphonic acid is,for example, aliphatic sulphonyloxy, such as methane-, ethane- andethenesulphonyloxy, or benzenesulphonyloxy which is unsubstituted orsubstituted by lower alkyl, halogen and/or nitro, for example benzene-,p-toluene- or p-bromobenzene-sulphonyloxy. Ammonium groups arepreferably quaternary ammonium groups, such as tri-lower alkylammonium,for example triethylammonium, or quaternary ammonium groups ofheteroaromatic bases, for example, of pyridinium. Sulphonium groups are,for example, di-lower alkylsulphonium groups, for exampledimethylsulphonium.

The condensation is carried out in customary manner, for example in thepresence of an inert solvent, if necessary in the presence of acondensation agent while cooling or heating and/or under inert gas, suchas nitrogen. There come into consideration as condensation agentsespecially basic condensation agents, such as hydroxides, carbonates orbicarbonates of alkali metals and alkaline earth metals, for examplesodium, potassium or calcium hydroxide, or sodium or potassiumcarbonate, also tertiary organic nitrogen bases, such as tri-loweralkylamines, for example triethylamine, or tertiary nitrogenheteroaromates, for example pyridine or quinoline. The condensation ispreferably carried out in a temperature range of approximately from 0°to 120° C., especially at approximately from +10° to +100° C.

The starting materials of the formula II can be manufactured, forexample, by condensing a compound of the formula

    Y.sub.1 --alk.sub.1 --X--alk.sub.2 --Y.sub.1 '             (IV),

in which Y₁ is a group H--N(R₃)-- and Y₁ ' is a group --N(R₆)--H and inwhich the group --N(R₆)--H can be more readily phenalkylated than thegroup H--N(R₃)--, or a salt thereof, with a compound of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V)

in which Y₂ ' is a nucleophilically replaceable radical, for examplehalogen, preferably in the manner indicated above for the condensationof compounds of the formulae II and III. It is, however, also possibleto use as the starting material a compound of the formula IV in which Y₁and Y₁ ' are nucleophilically replaceable radicals Y, for examplehalogen, but Y₁ ' is more reactive than Y₁, and this compound can bereacted with a compound of the formula V in which Y₂ ' is a groupH--N(R₆)-- and R₆ is different from hydrogen. In one process variantwhich is especially suitable for the manufacture of compounds of theformula II in which Y₁ is a group H--N(R₃)-- and R₆ is the same as R₃and alk₂ is the same as alk₁, an excess, for example 5 to 10 times themolar amount, of a corresponding diamine of the formula IV (Y₁ ═Y₁'═--N(R₃)--H) is reacted with a halide of the formula V (Y₂ '=halogen)and the amine excess is separated off.

The intermediates of the formula II obtainable according to one of theabove methods of production can be reacted with the reactants of theformula III without being isolated.

Another variant of the above process for the production and furtherreaction of intermediates of the formula II which is especially suitablefor the manufacture of compounds of the formula I in which R₇ is thesame as R₂ and R₈ is the same as R₁ consists in reacting a compound ofthe formula IV in which Y₁ is a group H--N(R₃)-- and Y₁ ' is a group--N(R₆)--H with double the molar quantity of a compound of the formulaIII in which Y₂ is a nucleophilically replaceable radical Y, for examplehalogen, or, for the manufacture of compounds of the formula I in which,in addition, R₆ is the same as R₃, reacting a compound of the formula IVin which Y₁ and Y₁ ' are each a nucleophilically replaceable radical,for example halogen, with double the molar quantity of a compound of theformula III in which Y₂ is a group H--N(R₃)--.

The novel compounds of the formula I in which R₄ is a group of theformula --alk₁ --X--alk₂ --N(R₆)--CH(R₇)--R₈ can also be manufacturedby, in a compound of the formula

    R.sub.1 --Y.sub.3 --X'--Y.sub.4 --R.sub.8                  (VI)

in which Y₃ is a radical Y₃ ' that can be converted into a group of theformula --CH(R₂)--N(R₃)--alk₁ -- and X' is a group X or a radical X"that can be converted into methylene or Y₃ is a group of the formula--CH(R₂)--N(R₃)--alk₁ -- and X' is a radical that can be converted intomethylene and in which Y₄ is a group of the formula --alk₂--N(R₆)--CH(R₇)-- or a radical Y₄ ' that can be converted into thatgroup, or in a salt thereof, converting Y₃ ' into a group of the formula--CH(R₂)--N(R₃)--alk₁ '--, X" into methylene and/or Y₄ ' into a group ofthe formula --alk₂ --N(R₆)--CH(R₇)--, if necessary separating anisomeric mixture obtainable according to the process into its componentsand, if desired, converting a compound obtainable according to theprocess into a different compound of the formula I and/or converting afree compound obtainable according to the process into a salt orconverting a salt obtainable according to the process into the freecompound or into a different salt.

There come into consideration as radicals Y₃ ', for example, those ofthe formulae --C(═Y₆)--N(R₃)--alk₁ --, --CH(R₂)N(R₃)--C(═Y₆)--,--C(Y₅)(R₂)--N(R₃)--alk₁ --, --CH(R₂)--N(R₃)--alk₁ '--, C(R₂)═N--alk₁ --and --CH(R₂)--N═alk"--, as radicals X", for example, those of theformulae --CH(Y₅)-- and --C(═Y₆)-- and as radicals Y₄ ' those of theformulae --alk₂ --N(R₆)--C(═Y₆)--, --C(═Y₆)--N(R₆)--CH(R₇)--, --alk₂--N(R₆)--C(Y₅) (R₇)--, alk₂ '--N(R₆)--CH(R₇)--, alk₂ --N═C(R₇)-- and--alk"═N--CH(R₇)--, in which Y₅ is a monovalent and Y₆ a divalentradical replaceable by hydrogen, alk₁ ' and alk₂ ' are lower alkylidenesubstituted by at least one radical Y₅ and Y₆, respectively, and alk" islower alkylidine. Radicals Y₅ are, for example, unmodified orfunctionally modified hydroxy or mercapto groups, also organic sulphonylgroups and carboxy. Radicals Y₆ are, for example, oxo groups orfunctionally modified oxo groups that are bonded via a double bond.

Functionally modified hydroxy groups are, for example, etherified oresterified hydroxy groups while there come into consideration asfunctionally modified mercapto groups especially etherified mercaptogroups. Etherified hydroxy groups are, for example, lower alkoxy groups,such as methoxy or ethoxy. Esterified hydroxy groups are, for example,hydroxy groups esterified by a mineral acid or an organic carboxylic orsulphonic acid. Organic carboxylic acids are, for example, unsubstitutedor substituted benzoic acids or lower alkanecarboxylic acids, forexample benzoic or acetic acid. Organic sulphonic acids are, forexample, benzene-, p-toluene-, p-bromobenzene-, methane-, ethane- orethene-sulphonic acid. Mineral acids are preferably hydrohalic acids,for example hydrochloric, hydrobromic or hydriodic acid. Etherifiedmercapto groups are, for example, lower alkylated or lower alkenylatedmercapto groups, such as methylthio, ethylthio or ethylenethio.

Functionally modified oxo groups are, for example, thiono groups,semicarbazono groups or hydrazono groups that are unsubstituted orsubstituted in the β-position by organic sulphonyl, such as benzene-,p-toluene-, p-bromobenzene- or methane-sulphonyl.

The conversion of Y₃ ', X" and, optionally, Y₄ ', into the groupsmentioned is carried out in a manner known per se, for example byreduction, i.e. reaction with a suitable reducing agent. As such therecome into consideration, for example: nascent hydrogen, for examplehydrogen produced by the action on metals of a compound having labilehydrogen, for example a protonic acid, such as a hydrophalic acid orlower alkanecarboxylic acid, on iron or unamalgamated or amalgamatedzinc, magnesium or aluminium, or by the action of water on, preferablyamalgamated, aluminium, magnesium or sodium, for example on sodiumamalgam, or, for example, hydrogen that is catalytically activated by ahydrogenation catalyst, such as a nickel or noble metal catalyst, forexample Raney nickel or platinum that may be in a form that ischemically bonded or bonded to a carrier, for example in the form of anoxide, such as hydrogen catalytically activated by platinum-on-carbon orplatinum oxide, or by homogenous noble metal catalysts, such astriphenylphosphineplatinum chloride or triphenylphosphine-rhodiumchloride, and there also come into consideration low-valency transitionmetal compounds, such as tin(II) or chromium(II) salts, for exampletin(II) chloride, or hydrides, such as calcium hydride, the boronhydride/tetrahydrofuran complex, or the complex consisting of9-butyl-9-borabicyclo[3,3,1]nonane and butyllithium, or di-light metalhydrides, such as lithium aluminium hydride, that may be in admixturewith aluminium chloride, sodium bis-(2-methoxyethoxy)-aluminium hydrideor sodium tris-(2-dimethylaminoethoxy)-aluminium hydride, sodiumborohydride, lithium triethyl borohydride or sodium cyanoborohydride inhexamethylphosphoric acid triamide.

The reaction can be carried out in the manner known from the literatureto be suitable in each case.

For example, groups Y₃ ', X" and/or Y₄ ' having free or esterified orfree or etherified hydroxy groups Y₅ bonded to a benzylic carbon atomand also having ketonic oxo groups Y₆ can be reduced especially bycustomary reaction with hydrogen that is catalytically activated, forexample as indicated above, for example with hydrogen in the presence ofpalladium-on-carbon, if necessary in an inert solvent, such as a loweralkanol, a lower alkanoic acid or an aliphatic ether, for example inethanol, acetic acid or dioxan, and/or at elevated temperature.

Radicals Y₃ ' and/or Y₄ ' having ketonic oxo groups, sulphonyloxy groupsand/or etherified mercapto groups can also be reduced by customaryreaction with nascent hydrogen, for example hydrogen produced asindicated above, for example according to Clemmensen's method,preferably with zinc and hydrochloric acid.

Radicals Y₃ ', X" and/or Y₄ ' having halogen, free or etherifiedhydroxy, at least one C--N double bond and/or amidic oxo groups can bereduced, for example, by customary reaction with a suitable di-lightmetal hydride, such as one of those mentioned, if necessary in an inertsolvent and/or at elevated temperature, for example at boilingtemperature, starting from halogen compounds, for example with sodiumborohydride in water, alcohols, such as ethanol, or ethylene glycolmonomethyl ether, or amines, such as pyridine or triethylamine, or withlithium triethyl borohydride, sodium bis-(2-methoxyethoxy)-aluminiumhydride in aromatic or araliphatic hydrocarbons, such as benzene ortoluene, or with sodium tris-(dimethylaminoethoxy)-aluminium hydride, orstarting from lactams or amides, for example with lithium aluminiumhydride in an aliphatic ether, for example in diethyl ether,tetrahydrofuran or dioxan, if necessary at boiling temperature.

Radicals Y₃ ', X" and/or Y₄ ' having hydrazono groups substituted asindicated, for example β-(p-toluenesulphonyl)-hydrazono, can be replacedby hydrogen especially by customary reaction with a di-light metalhydride, for example with sodium cyanoborohydride inhexamethylphosphoric acid triamide, if necessary at elevatedtemperature. Radicals X", Y₃ ' and/or Y₄ ' having semicarbazono orunsubstituted hydrazono groups can be reduced, for example, by customaryreaction with a strong base, for example, according to the Wolff-Kishnermethod, with an alkali metal alcoholate, for example with sodiummethoxide, if necessary under elevated pressure and/or at elevatedtemperature, or, according to the Huang-Minlon modification, with analkali metal hydroxide, for example potassium hydroxide, in an inert,high-boiling solvent, for example in di- or tri-ethylene glycol ordiethylene glycol monomethyl ether.

Azomethine groups of the formulae --C(R₂)═N--alk₁ -- and--CH(R₂)--N═alk"-- and/or --alk₂ --N═C(R₇)-- and --alk"═N--CH(R₇)-- canbe reduced, for example, by catalytically activated hydrogen, such aswith hydrogen in the presence of platinum oxide in ethanol at normal orslightly elevated pressure, for example at approximately from 0 to 10bar overpressure, or with hydrogen in the presence of Raney nickel atelevated pressure, for example at approximately from 20 to 150 bar,preferably approximately 100 bar, overpressure, by reaction with lithiumaluminium hydride, preferably in tetrahydrofuran, or by means of nascenthydrogen or by metallic reduction, for example by treatment with zincand acetic acid, iron and hydrochloric acid and the like.

Starting from azomethine compounds of the formula VI in which Y₃ ' is agroup of the formula --CH═N--alk₁ -- or --CH(R₂)--N═alk"-- and/or Y₄ 'is a group of the formula --alk₂ --N═CH-- or --alk"═N--CH(R₂)--, therecome into consideration as further reducing agents also lower alkylmetal compounds, and, starting from compounds of the formula VI in whichY₃ ' is a group of the formula --CH═N--alk₁ -- and/or Y₄ ' is a group ofthe formula --alk₂ N═CH--, also phenyl metal compounds which may also besubstituted by aliphatic and/or cyclo-aliphatic radicals, etherifiedhydroxy, di-lower alkyl- or lower alkylene-amino and/or trifluoromethyl."Metal compounds" should in this case be understood as meaning, forexample, alkali metal compounds, such as lithium and sodium compounds,and also halo-magnesium compounds, such as bromo-, chloro- oriodo-magnesium compounds. The reaction with such metal compounds iscarried out in the customary manner, for example in a di-lower alkylether or a lower alkylene ether, for example in diethyl ether,tert-butoxymethane, dioxan or tetrahydrofuran, if necessary whilecooling or heating, for example at approximately from 0° to 100° C.,and/or under inert gas, such as nitrogen.

In a preferred embodiment of the above process, there is used asstarting material, for example, a compound of the formula VI in which Y₃is a group --C(═O)--N(R₃)--alk₁ '-- or --CH(R₂)--N(R₃)--C(═O)-- and Y₄is a group --alk₂ --N(R₆)--CH(R₇)--, --alk₂ --N(R₆)--C(═O)-- or--C(═O)--N(R₆)--CH(R₇)-- and the oxo group(s) is(are) reduced, forexample, by reaction with a suitable di-light metal hydride, for examplewith lithium aluminium hydride in an ether, for example in diethyl etheror tetrahydrofuran, if necessary at elevated temperature, for example atboiling temperature.

In another preferred embodiment of the above process, there is used asstarting material, for example, a compound of the formula VI in which Y₃is a group of the formula --C(R₂)═N--alk₁ -- and Y₄ is a group of theformula --alk₂ --N(R₆)--CH(R₇)-- or --alk₂ --N═C(R₇)-- and the C-Ndouble bond(s) is(are) reduced, for example, by means of hydrogen in thepresence of platinum oxide at approximately from 20° to 30° C. andapproximately from 0.5 to 1.25 bar, or by reaction with lithiumaluminium hydride in tetrahydrofuran, preferably at approximately from60° C. to boiling temperature.

A further radical Y₅ replaceable by hydrogen is the carboxy group whichmay be in salt form, for example in the form of an alkali metal salt,such as sodium salt, or a copper or ammonium salt. The carboxy group isreplaced by hydrogen preferably by decarboxylation, for example byheating to approximately from 100° to 250° C., if necessary in ahigh-boiling solvent, for example in ethylene glycol, dimethylformamide,ethylene glycol monomethyl ether or diphenylether.

Further radicals that can be converted into groups of the formula--CH(R₂)--N(R₃)--alk₁ -- and --alk₂ --N(R₆)--CH(R₇)-- in which R₂ and R₆are hydrogen are those of the formula --CH(R₂)N(Y₇)--alk₁ -- and --alk₂--N(Y₇)--CH(R₇)--, respectively, in which Y₇ is a monovalent radicalreplaceable by hydrogen. In compounds of the formula VI in which X' ismethylene, a direct bond or o-phenylene that is unsubstituted orsubstituted as indicated, there come into consideration as furtherradicals that can be converted into the group of the formula--CH(R₂)--NH--alk₁ --X'--alk₂ --NH--CH(R₇)-- those of the formula##STR1## in which Y₈ is a divalent radical replaceable by hydrogen.

Monovalent radicals Y₇ replaceable by hydrogen are, for example, acylgroups, triarylmethyl groups, 2-acyl-lower alk-1-enyl radicals and silylgroups. Divalent radicals replaceable by hydrogen are, for example,carbonyl and thiocarbonyl groups.

Acyl groups are, for example, acyl groups derived from an organiccarboxylic acid having, for example, up to 18 carbon atoms, especiallyan alkanecarboxylic acid that is unsubstituted or substituted, forexample, by halogen or aryl, or benzoic acid that is unsubstituted orsubstituted, for example, by halogen, lower alkoxy or nitro, or from acarbonic acid semiester. Such acyl groups are, for example, loweralkanoyl, such as formyl, acetyl or propionyl, halo-lower alkanoyl, suchas 2-haloacetyl, especially 2-chloro-, 2-bromo-, 2-iodo-,2,2,2-trifluoro- or 2,2,2-trichloroacetyl, benzoyl that is unsubstitutedor substituted, for example, by halogen, lower alkoxy or nitro, forexample benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-nitrobenzoyl, orlower alkoxycarbonyl that is branched in the 1-position of the loweralkyl radical or suitably substituted in the 1- or 2-position,especially tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl,arylmethoxycarbonyl having one or two aryl radicals which are preferablyphenyl that is unsubstituted or mono- or poly-substituted, for example,by lower alkyl, especially tert-lower alkyl, such as tert-butyl, loweralkoxy, such as methoxy, hydroxy, halogen, for example chlorine, and/orby nitro, such as unsubstituted or substituted benzyloxycarbonyl, forexample 4nitrobenzyloxycarbonyl, or substituted diphenylmethoxycarbonyl,aroylmethoxycarbonyl in which the aroyl group is preferably benzoyl thatis unsubstituted or substituted, for example, by halogen, such asbromine, for example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl,for example 2,2,2-trichloroethoxycarbonyl, 2-bromoethoxycarbonyl or2-iodoethoxycarbonyl, or 2-(tri-substituted silyl)-ethoxycarbonyl inwhich each of the substituents represents, independently of one another,an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbonradical that has, for example, up to 15 carbon atoms and isunsubstituted or substituted, for example, by lower alkyl, lower alkoxy,aryl, halogen or nitro, such as corresponding unsubstituted orsubstituted lower alkyl, phenyl-lower alkyl, cycloalkyl or phenyl, forexample 2-tri-lower alkylsilylethoxycarbonyl, such as2-trimethylsilylethoxycarbonyl or2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or2-triarylsilylethoxycarbonyl, such as 2-triphenylsilylethoxycarbonyl.

Further acyl radicals Y₇ are also corresponding radicals of organicphosphoric, phosphonic or phosphinic acids, such as di-loweralkylphosphoryl, for example dimethylphosphoryl, diethylphosphoryl,di-n-propylphosphoryl of diisopropylphosphoryl, dicycloalkylphosphoryl,for example dicyclohexylphosphoryl, unsubstituted or substituteddiphenylphosphoryl, for example diphenylphosphoryl, diphenylloweralkylphosphoryl that is unsubstituted or substituted, for example, bynitro, for example dibenzylphosphoryl or di-4-nitrobenzylphosphoryl,unsubstituted or substituted phenyloxyphenylphosphonyl, for examplephenyloxyphenylphosphonyl, di-lower alkylphosphinyl, for examplediethylphosphinyl, or unsubstituted or substituted diphenylphosphinyl,for example diphenylphosphinyl.

In a triarylmethyl group the aryl radicals are especially unsubstitutedor substituted phenyl radicals. Such a group is especially trityl.

In a 2-acyl-lower alk-1-en-1-yl radical, acyl is, for example, thecorresponding radical of a lower alkanecarboxylic acid, of a benzoicacid that is unsubstituted or substituted, for example, by lower alkyl,such as methyl or tert-butyl, lower alkoxy, such as methoxy, halogen,such as chlorine, and/or nitro, or especially of a carbonic acidsemiester, such as a carbonic acid lower alkyl semiester. Correspondingprotecting groups are especially 1-lower alkanoylprop-1-en-2-yl, forexample 1-acetylprop-1-en-2-yl, or 1-lower alkoxycarbonylprop-1-en-2-yl,for example 1-ethoxycarbonylprop-1-en-2-yl.

A silyl group is especially an organic silyl group in which the siliconcontains as substituent preferably lower alkyl, especially methyl, alsolower alkoxy, for example methoxy, and/or halogen, for example chlorine.Corresponding silyl groups are especially tri-lower alkylsilyl,especially trimethylsilyl, also dimethyl-tert-butyl-silyl, loweralkoxylower alkyl-halo-silyl, for example methoxy-methyl-chlorosilyl, ordi-lower alkyl-halo-silyl, for example dimethylchloro-silyl.

Preferred groups Y₇ are acyl radicals of carbonic acid semiesters,especially tert-butoxycarbonyl, benzyloxycarbonyl that is unsubstitutedor substituted, for example, as indicated, for example4-nitrobenzyloxycarbonyl, or diphenylmethoxycarbonyl, or 2-halo-loweralkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, also trityl orformyl.

The removal of the mentioned groups Y₇ and Y₈ is carried out in thecustomary manner, for example by solvolysis, especially hydrolysis,alcoholysis or ammonolysis or aminolysis, respectively, or by reduction,especially be means of chemical reducing agents.

2-halo-lower alkoxycarbonyl (optionally after converting a 2-bromo-loweralkoxycarbonyl group into a2-iodo-lower alkoxycarbonyl group),aroylmethoxycarbonyl or 4-nitrobenzyloxycarbonyl can be removed, forexample, by treatment with a suitable chemical reducing agent, such aszinc in the presence of a suitable carboxylic acid, such as aqueousacetic acid. Aroylmethoxycarbonyl can also be cleaved by treatment witha nucleophilic, preferably salt-forming reagent, such as sodiumthiophenolate, and 4-nitrobenzyloxycarbonyl can also be cleaved bytreatment with an alkali metal dithionite, for example sodiumdithionite. Unsubstituted or substituted diphenylmethoxycarbonyl,tert-lower alkoxycarbonyl or 2-trisubstituted silylethoxycarbonyl can beremoved by treatment with a suitable acid, for example formic oftrifluoroacetic acid, unsubstituted or substituted benzyloxycarbonyl,for example, by means of hydrogenolysis, i.e. by mild treatment withhydrogen in the presence of a suitable hydrogenation catalyst, such as apalladium catalyst, unsubstituted or substituted triarylmethyl, formylor 2-acyl-lower alk-1-enyl, for example, by treatment with an acid, suchas a mineral acid, for example hydrochloric acid, or an organic acid,for example formic, acetic or trifluoroacetic acid, optionally in thepresence of water, and an organic silyl, for example, by means ofhydrolysis or alcoholysis. 2-haloacetyl, for example 2-chloroacetyl, canbe freed by treatment with thiourea in the presence of a base, or with athiolate salt, such as an alkali metal thiolate, of thiourea andsubsequent solvolysis, such as alcoholysis or hydrolysis, of theresulting condensation product. 2-substituted silylethoxycarbonyl canalso be removed by treatment with a salt of hydrofluoric acid yieldingfluoride ions, for example with potassium fluoride. A phosphoro,phosphono or phosphino group can be removed, for example, by treatmentwith a phosphorus-containing acid, such as a phosphoric, phosphonic orphosphinic acid, for example orthophosphoric acid or polyphosphoricacid, an acid ester, for example monomethyl, monoethyl, dimethyl ordiethyl phosphate, or monomethylphosphonic acid, or an anhydridethereof, such as phosphorus pentoxide.

The starting materials can be manufactured according to methods knownper se.

Thus, compounds of the formula VI in which Y₃ ' is a group of theformula --C(═Y₆)--N(R₃)--alk₁ -- are obtained, for example, bycondensing with one another according to conventional methods ofesteraminolysis, aminoacylation or transamidation compounds of theformulae

    R.sub.1 --C(═Y.sub.6)--Z                               (VII)

and

    H--N(R.sub.3)--alk.sub.1 --X'--Y.sub.4 --R.sub.8           (VIII)

in which Z is etherified or reactive esterified hydroxy or a quaternaryammonium group, for example lower alkoxy, halogen or pyridinium.Compounds of the formula VIII in which Y₄ is a group --alk₂--N(R₆)--CH(R₇)--R₈ can for their part be manufactured, for example, bycondensing with one another, for example as indicated for the reactionof compounds of the formulae II and III, compounds of the formulae

    Y.sub.1 --alk.sub.1 --X'--alk.sub.2 --Y.sub.1 '            (IX)

and

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V)

in which Y₁ is a group H--N(R₃)--, Y₁ ' is a nucleophilicallyreplaceable radical Y, for example halogen, and Y₂ ' is a groupH--N(R₆)--.

Compounds of the formula VI in which Y₃ ' is a group--C(═Y₆)--N(R₃)--alk₁ -- and Y₄ ' is a group --alk₂ --N(R₆)--C(═Y₆)--and in which R₇ is the same as R₂ and R₈ is the same as R₁, can bemanufactured, for example, by reacting a compound of the formula IX inwhich Y₁ is a group H--N(R₃)--and Y₁ ' is a group --N(R₆)--H with doublethe molar quantity of a compound of the formula V in which Y₂ ' is anucleophilically replaceable radical Y, for example halogen.

Starting from compounds of the formula IX in which Y₁ is a groupH--N(R₃)-- and Y₁ ' is a group --N(R₆)--H and in which one of these twogroups is more readily acylated than the other, it is possible first ofall to acylate a more readily acylatable group H--N(R₃)-- by reactionwith a compound of the formula VII or a more readily acylatable group--N(R₆)--H by reaction with a compound of the formula

    Z--(Y.sub.6 ═)C--R.sub.8                               (X)

and in the resulting compound of the formula IX in which Y₁ is a groupR₁ --C(═Y₆)--N(R₃)-- and Y₁ ' is a group --N(R₆)--H, or Y₁ is a groupH--N(R₃)-- and Y₁ ' is a group --N(R₆)--C(═Y₆)--R₈, respectively, tophenalkylate the group --N(R₆)--H or H--N(R₃)-- by reaction with acompound of the formula V or

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

respectively, in which Y₂ ' or Y₂, respectively, is a nucleophilicallyreplaceable radical Y, for example halogen, or to acylate it by reactionwith a compound of the formula X or VII, respectively. It is, however,alternatively possible first of all to phenalkylate the more readilyphenalkylatable group H--N(R₃)-- or --N(R₆)--H by reaction with thecompound of the formula III or V, respectively, and then to acylate theprimary product by reaction with the compound of the formula X or VII,respectively.

In an analogous manner, starting materials of the formula VI in which Y₃' is a group --CH(R₂)--N(R₃)--C(═Y₆)--and Y₄ ' is a group --alk₂--N(R₆)--CH(R₇)--, --C(═Y₆)--N(R₆)--CH(R₇)--or --alk₂--N(R₆)--C(═Y₆)--(R₇)--, are also obtained by reacting a compound of theformula

    Z.sub.1 --C(═Y.sub.6)--X'--C(═Y.sub.6)--Z.sub.2    (XI)

in which Z₁ and Z₂ are, independently of one another, free or etherifiedor free or reactive esterified hydroxy, such as hydroxy, lower alkoxy orhalogen, or, if X' is unsubstituted or substituted o-phenylene and Y₆ isoxo, they are together oxy, first of all with an amine of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is --N(R₃)--H, and then with an amine of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is H--N(R₆)--, or reacting a compound of the formula

    Z.sub.1 --C(═Y.sub.6)--alk.sub.2 --N(R.sub.6)--H       (XII)

first of all with a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is --N(R₃)--H, and then with a compound of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is a nucleophilically replaceable radical Y, for examplehalogen, or with a compound of the formula X.

Compounds of the formula VI in which Y₃ is a group --C(OH)(R₂)--N(R₃)--alk₁ -- or --CH(R₂)--N(R₃)--alk₁ '--(alk₁ '═α-hydroxy-loweralkylidene) are advantageously manufactured in situ, for example byreacting a compound of the formula VIII under reducing conditions, forexample in the presence of formic acid or one of its salts or in thepresence of hydrogen activated, for example, by platinum or platinumcompounds, preferably in acidic media, for example in acetic acidsolution, with a compound of the formula

    (R.sub.1)(R.sub.2)C(═O)                                (XIII)

or reacting a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III).

in which Y₂ is --N(R₃)--H with a compound of the formula

    O═alk"--X'--Y.sub.4 --R.sub.8                          (XIV)

The compound of the formula VI, which is formed as the primary product,is in this case reduced according to the process directly to form thedesired end product or, if R₃ is hydrogen, via the azomethine (Y₃═--C(R₂)═N--alk₁ -- or --CH(R₂)--N═alk₁ "--, respectively).

As an alternative to this process variant, for the manufacture ofcompounds of the formula I in which R₇ is the same as R₂ and R₈ is thesame as R₁, a compound of the formula

    Y.sub.1 --alk.sub.1 --X--alk.sub.2 --Y.sub.2               (IV),

in which Y₁ is a group H--N(R₃)-- and Y₁ ' is a group --N(R₆)--H, canadvantageously be reacted with double the molar quantity of a compoundof the formula XIII or, for the manufacture of compounds of the formulaI in which, in addition, R₆, is the same as R₃, a compound of theformula

    O═alk"--X--alk"═O                                  (XV)

can be reacted with double the molar quantity of a compound of theformula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is H--N(R₃). In this process, an intermediate of the formulaVI is formed in which, in the first case, Y₃ is a group--C(OH)(R₂)--N(R₃)--alk₁ -- or, if R₃ is H, a group --C(R₂)═N--alk₁ --,and Y₄ is a group --alk₂ --N(R₃)--C(OH)(R₇)-- or, if R₆ is H, a group--alk₂ --N═C(R₇)--, or, in the second case, in which Y₃ is a group--CH(R₂)--N(R₃)--alk₁ '--or, if R₃ is H, a group --CH(R₂)--N═alk₁ " andY₄ is a group --alk₂ '--N (R₆)--CH(R₇)-- or, if R₆ is H, a group --alk₂"═N--CH(R₇)--, which intermediate is then reduced according to theprocess.

Compounds of the formula VI in which Y₃ ' is a group --C(R₂)═N--alk₁ --or --CH(R₂)--N═alk₁ "-- are obtained by condensing, in customary manner,for example in the presence of an acid catalyst, for examplep-toluenesulphonic acid, a compound of the formula

    H--N(R.sub.3)--alk.sub.1 --X--Y.sub.4 --R.sub.8            (VIII),

in which R₃ is hydrogen, or a salt thereof, with a compound of theformula

    (R.sub.1)(R.sub.2)C(═O)                                (XIII)

or condensing a compound of the formula

    O═alk.sub.1 "--X--Y.sub.4 --R.sub.8                    (XIV)

with a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is a group --NH₂, or with a salt thereof. Compounds of theformula VIII in which Y₄ is a group --alk₂ "═N--CH(R₇)-- can beobtained, for example, by reacting a compound of the formula

    H.sub.2 N--alk.sub.1 --X--alk.sub.2 "═0                (XVI)

with a compound of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is amino. Compounds of the formula XIV in which Y₄ is agroup --alk₂ --N═C(R₇)-- can be manufactured in an analogous manner byreacting a compound of the formula

    H.sub.2 N--alk.sub.1 --X--alk.sub.2 '═0                (XVII)

with a compound of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is amino, and then with a compound of the formula XIII.According to one of these production methods, aromethines of the formulaVI can be synthesised in steps. For the manufacture of symmetricaromethines of the formula VI in which R₇ is the same as R₂ and R₈ isthe same as R₁ practical advantages are obtained, however, by thevariant according to which either a compound of the formula

    Y.sub.1 --alk.sub.1 --X--alk.sub.2 --Y.sub.1 '             (IV),

in which Y₁ and Y₂ are amino, or a salt thereof, is reacted with doublethe molar quantity of a compound of the formula

    (R.sub.1)(R.sub.2)C(═0)                                (XIII)

or a compound of the formula

    0═alk.sub.1 --X--alk.sub.2 ═0                      (XV)

is reacted with double the molar quantity of a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is amino, or with a salt thereof.

Compounds of the formula VI in which X' is a radical X" of the formula--CH(Y₅)-- or --C(═Y₆)-- that can be converted into methylene can bemanufactured, for example, by condensing with one another, especially inthe manner indicated for the reaction of compounds of the formulae IIand III, compounds of the formulae

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III)

and

    Y.sub.1 --alk.sub.1 --X"--alk.sub.2 --N(R.sub.6)--CH(R.sub.7)--R.sub.8(XIX)

in which one of the radicals Y₁ and Y₂ is a group H--N(R₃) and the otheris a nucleophilically replaceable radical, for example halogen.Compounds of the formula XIX in which Y₁ is halogen and X" is a group--C(═0)-- are obtained, for example, by reacting a compound of theformula

    H--alk.sub.1 --C(═0)--alk.sub.2 --Y                    (XX)

in which Y is a nucleophilically replaceable radical, for examplehalogen, with a compound of the formula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is a group H--N(R₆)-- and halogenating the reactionproduct in the α-position of the group H--alk₁ --, for example by theaction of bromine. Compounds of the formula VI in which alk₂ ismethylene and X" is a group --CH(OH)-- can be obtained by reacting acompound of the formula ##STR2## in which Y is a nucleophilicallyreplaceable radical, for example halogen, first with a compound of theformula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III)

in which Y₂ is a group --N(R₃)--H and then with a compound of theformula

    Y.sub.2 '--CH(R.sub.7)--R.sub.8                            (V),

in which Y₂ ' is a group H--N(R₆)--.

For the manufacture of compounds of the formula VI in which X' is agroup X" and in which R₇ is the same as R₂ and R₈ is the same as R₁ itis advantageous to combine both production steps by reacting compoundsof the formulae

    R.sub.1 CH(R.sub.2)--Y.sub.2                               (III)

and

    Y.sub.1 --alk.sub.1 --X"--alk.sub.2 --Y.sub.1 '            (XXII)

in which Y₂ is a radical Y, Y₁ is a group H--N(R₃)-- and Y₁ ' is a group--N(R₆)--H, or for the manufacture of compounds in which R₆ is the sameas R₃, by reacting compounds of the formulae V and XXII in which Y₂ is agroup --N(R₃)--H and Y₁ and Y₁ ' are radicals Y, Y being anucleophilically replaceable radical, such as halogen.

Starting materials of the formula VI in which Y₃ is a group of theformula --CH(R₂)--N(R₃)--alk₁ --, X' is a group X and Y₄ is a group ofthe formula --alk₂ --N(Y₇)--CH(R₇)-- can be manufactured, for example,by reacting a compound of the formula

    Y.sub.1 --alk.sub.1 --X--alk.sub.2 --Y.sub.1 '             (IV),

in which Y₁ is hydroxy and Y₁ ' is a nucleophilically replaceableradical, for example halogen, with a compound of the formula

    H--N(Y.sub.7)--CH(R.sub.7)--R.sub.8                        (XXIII)

reactively esterifying the hydroxy group Y₁ in the condensation productformed, for example by reaction with thionyl chloride, phosphorustribromide or an organic sulphonyl chloride, such as p-toluenesulphonylchloride, and then reacting with a compound of the formula

    R.sub.1 --CH(R.sub.2)--Y.sub.2                             (III),

in which Y₂ is a group --N(R₃)--H. As an alternative to this process, itis, however, also possible to use as starting materials compounds of theformula IV in which Y₁ and Y₁ ' are nucleophilically replaceableradicals, for example halogen, and in which alk₁ is the same as alk₂ orY₁ ' is more reactive than Y₁.

Starting materials of the formula VI in which Y₃ --X'--Y₄ is a group ofthe formula VIa can be manufactured, for example, by reacting a compoundof the formula ##STR3## in which alk₁ is the same as alk₂ first with acompound of the formula V and then with a compound of the formula III inwhich Y₂ ' and Y₂, respectively, are nucleophilically replaceableradicals, for example halogen.

Compounds obtainable according to the invention can be converted in amanner known per se into different compounds of the formula I in whichR₄ is a group of the formula --alk₁ --X--alk₂ --H(R₆)--CH(R₇)--R₈.

For example, in a compound obtainable according to the invention inwhich R₃ and R₆ are hydrogen, R₃ can be replaced by lower alkyl and R₆by lower alkyl or unsubstituted or substituted phenyl-lower alkyl, forexample by reaction with a reactive lower alkyl ester or phenyl-loweralkyl ester. Reactive lower alkyl esters are, for example, lower alkylhalides, such as lower alkyl chlorides, bromides or iodides, loweralkylsulphonates, for example lower alkyl-lower alkanesulphonates, suchas lower alkyl methanesulphonates or ethanesulphonates, loweralkylbenzenesulphonates, such as lower alkylbenzenesulphonates, loweralkyl-p-toluenesulphonates or -p-bromosulphonates, also loweralkylfluorosulphonates, or di-lower alkyl sulphates. The reaction withthe mentioned reactive esters is carried out, for example, in thepresence of a basic condensation agent, if necessary in an inertsolvent, in vacuo or while heating and/or under inert gas, such asnitrogen. Basic condensation agents are, for example, hydroxides orcarbonates of an alkali metal or alkaline earth metal, for examplesodium, potassium or calcium hydroxide, sodium or potassium carbonate,or tertiary organic nitrogen bases, such as tri-lower alkylamines, forexample triethylamine or diisopropylmethylamine, or heteroaromaticnitrogen bases, for example pyridine. Inert solvents are, for example,lower alkanols, such as methanol, butanol or amyl alcohol, di-loweralkyl ketones, such as acetone, di-lower alkyl ethers or lower alkyleneethers, such as tert-butoxymethane, dioxan or tetrahydrofuran, loweralkanoic acid amides or lactams, such as dimethylformamide orN-methylpyrrolidone, and di-lower alkyl sulphoxides, for exampledimethyl sulphoxide, and also mixtures of the same with one anotherand/or with water. The replacement of hydrogen R₃ or R₆ by lower alkylor of hydrogen R₆ by phenylalkyl can, however, also be carried out byreaction with a lower alkanal or phenyl-lower alkanal, respectively, inthe presence of a reducing agent, for example formic acid or one of itssalts.

Furthermore, for example, a free carboxyl group R₂ and/or R₇ can beconverted into an esterified carboxyl group R₂ and/or R₇ in customarymanner, for example by reaction with the corresponding alcohol or areactive derivative, such as a carboxylic acid ester, phosphorous acidester, sulphurous acid ester or carbonic acid ester, for example a loweralkanecarboxylic acid ester, tri-lower alkyl phosphite, di-lower alkylsulphite or the pyrocarbonate of the corresponding alcohol, adiazo-lower alkane, for example with diazomethane, an olefin, such aslower alkene, or an amide acetal, such as a lower alkanecarboxylic acidamide di-lower alkyl acetal, for example with dimethylformamide diethylacetal.

The reaction with the corresponding alcohol itself is advantageouslycarried out in the presence of an acid catalyst, such as a protonicacid, for example hydrochloric or hydrobromic acid, sulphuric acid,phosphoric acid, boric acid, benzenesulphonic acid and/ortoluenesulphonic acid, or a Lewis acid, for example boron trifluorideetherate, in an inert solvent, especially an excess of the alcohol usedand, if necessary, in the presence of a water-binding agent and/or whileremoving the reaction water by distillation, for example azeotropically,and/or at elevated temperature.

The reaction with a reactive derivative of the corresponding alcohol canbe carried out in customary manner starting from a carboxylic,phosphorous, sulphurous or carbonic acid ester, for example in thepresence of an acid catalyst, such as one of those mentioned above, inan inert solvent, such as an aromatic hydrocarbon, for example inbenzene or toluene, or in an excess of the alcohol derivative used or ofthe corresponding alcohol. The reaction with amide acetals isadvantageously carried out under neutral conditions, for example inacetonitrile or dimethylformamide as the solvent.

The reaction with an olefin can be carried out, for example, in thepresence of an acid catalyst, for example a Lewis acid, for exampleboron trifluoride, a sulphonic acid, for example p-toluenesulphonicacid, or especially of a basic catalyst, for example sodium or potassiumhydroxide, advantageously in an inert solvent, such as an ether, forexample in diethyl ether or tetrahydrofuran.

The conversions described above of free carboxyl groups into esterifiedcarboxyl groups can, however, alternatively be carried out by firstconverting in customary manner a compound of the formula I in which R₂and/or R₇ are(is) carboxyl into a reactive derivative, preferablystarting from a bis-acid addition salt by reaction with a halide ofphosphorus or sulphur, for example with phosphorus trichloride ortribromide, phosphorus pentachloride or thionyl chloride, to convert itinto an acid halide, or by reaction with a corresponding alcohol oramine to convert it into a reactive ester, i.e. an ester withelectron-attracting structures, such as an ester with phenol,thiophenol, p-nitrophenol, 2,4-dinitrophenol or cyanomethyl alcohol, ora reactive amide for example the amide derived from imidazole or3,5-dimethylpyrazole, and then reacting the resulting reactivederivative with a corresponding alcohol in customary manner, preferablyunder neutral or acidic conditions.

An esterified carboxyl group R₂ and/or R₇ can be transesterified incustomary manner, for example by reaction with a metal salt, such as thesodium or potassium salt, of a corresponding alcohol or with the alcoholitself in the presence of a catalyst, for example a strong base, forexample sodium or potassium hydroxide, or a strong acid, such as amineral acid, for example hydrochloric acid, sulphuric acid orphosphoric acid, or an organic sulphonic acid, for examplep-toluenesulphonic acid, or a Lewis acid, for example boron trifluorideetherate, to form a different esterified carboxyl group.

The novel compounds may, depending on the starting materials and methodschosen, be in the form of one of the possible isomers or a mixture ofthe same, for example, depending on the number of asymmetric carbonatoms, in the form of pure optical isomers such as antipodes, or in theform of isomeric mixtures, such as racemates, diastereoisomeric mixturesor racemate mixtures.

Because of the physico-chemical differences between their components,diastereoisomeric mixtures and racemate mixtures can be separated inknown manner into the pure isomers, diastereoisomers or racemates, forexample by chromatography and/or fractional crystallisation.

Resulting racemates can also be resolved into the optical antipodesaccording to known methods, for example by recrystallisation from anoptically active solvent, with the aid of microorganisms, or by reactionwith an optically active acid that forms salts with the racemic base,and separation of the salts obtained in this manner, for example on thebasis of their different solubilities, into the diastereoisomers fromwhich the antipodes can be freed by the action of suitable agents.Advantageously, the more active of the two antipodes is isolated.

Resulting free compounds of the formula I in which R₄ is a group of theformula --alk₁ --X--alk₂ --N(R₆)--CH(R₇)--R₈ can be converted into saltsin a manner known per se, inter alia by treatment with an acid, or,starting from an acid (R₂ and/or R₇ =carboxy), with a base or with asuitable salt of a carboxylic acid, generally in the presence of asolvent or diluent.

Resulting salts can be converted in a manner known per se into the freecompounds, for example by treatment with a basic or acidic reagent, suchas an alkali metal hydroxide or a mineral acid, respectively.

The compounds, including their salts, can also be obtained in the formof their hydrates or include the solvent used for crystallisation.

Owing to the close relationship between the novel compounds in free formand in the form of their salts, hereinbefore and hereinafter there shalloptionally be understood by free compounds and salts, where appropriatewith regard to meaning and purpose, also the corresponding salts andfree compounds, respectively.

The invention also relates to those embodiments of the process accordingto which a compound obtainable as an intermediate at any stage of theprocess is used as starting material and the remaining process steps arecarried out or a starting material is used in the form of a salt and/orracemate or antipode or, especially, is formed under the reactionconditions.

In the process of the present invention, the starting materials used arepreferably those that result in the compounds described at the beginningas being especially valuable. The present invention also relates tonovel starting materials and processes for their manufacture.

Pharmaceutical preparations that contain one of the compounds of theformula I according to the invention or a pharmaceutically acceptablesalt thereof are, for example, those that are intended for enteral, suchas oral or rectal, and parenteral, such as intravenous, administrationto, and for inhalation by, warm-blooded animals and that contain thepharmacological active ingredient alone or together with apharmaceutically acceptable carrier. The dosage of the active ingredientdepends on the species of the warm-blooded animal, the age and theindividual condition, and on the method of adminstration, but also onthe molar weight of the active ingredient. For example, there come intoconsideration for a warm-blooded animal weighing approximately 75 kgdaily doses of from approximately 1 to approximately 25, preferably fromapproximately 4 to approximately 20, especially from approximately 5 toapproximately 15, mg (based on the free base), which doses may, ifnecessary, be divided up into several, for example up to 4, preferablyup to 3, individual doses.

The novel pharmaceutical preparations contain, for example, fromapproximately 1% to approximately 50%, preferably from approximately 4%to approximately 20%, by weight of the active ingredient. Pharmaceuticalpreparations according to the invention are, for example, those in unitdosage forms, preferably in oral unit dosage form, such as dragees,tablets, capsules or suppositories, also ampoules, preparations in oralunit dosage form containing in each case, for example, fromapproximately 2 to approximately 25, especially approximately from 5 to15 mg, of active ingredient.

The pharmaceutical preparations of the present invention aremanufactured in a manner known per se, for example by means ofconventional mixing, granulating, confectioning, dissolving orlyophilising processes. For example, pharmaceutical prepartions for oraladministration can be obtained by combining the active ingredient withsolid carriers, optionally granulating a resulting mixture, andprocessing the mixture or granulate, if desired or necessary after theaddition of suitable adjuncts, to form tablets or dragee cores.

Suitable carriers are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, also binders, such as starch pastes, for example maize,wheat, rice or potato starch paste, gelatin, tragacanth, methylcelluloseand/or polyvinylpyrrolidone, and/or, if desired, disintegrators, such asthe above-mentioned starches, also carboxymethyl starch, cross-linkedpolyvinylpyrrolidone, agar, alginic acid or a salt thereof, such assodium alginate. Adjuncts are especially flow-regulating agents andlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium or calcium stearate, and/or polyethylene glycol.Dragee cores are provided with suitable coatings which are optionallyresistant to gastric juices, there being used, inter alia, concentratedsugar solutions, which may contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or solvent mixtures, or,for the manufacture of coatings resistant to gastric juices, solutionsof suitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate. Colouring substances or pigmentsmay be added to the tablets or dragee coatings, for example foridentification or for distinguishing different doses of the activeingredient.

Further orally administrable pharmaceutical preparations are dry-filledcapsules made of gelatin, and also soft, sealed capsules made of gelatinand a plasticiser, such as glycerine or sorbitol. The dry-filledcapsules may contain the active ingredient in the form of a granulate,for example in admixture with fillers, such as lactose, binders, such asstarches, and/or glidants, such as talc or magnesium stearate, andoptionally with stabilisers. In soft capsules the active ingredient ispreferably dissolved or suspended in suitable liquids, such as fattyoils, paraffin oil, or liquid polyethylene glycols, it likewise beingpossible for stabilisers to be added.

There come into consideration as rectally administrable pharmaceuticalpreparations, for example, suppositories that consist of a combinationof the active ingredient and a suppository base substance. Suitable as asuppository base substance are, for example, natural or synthetictriglycerides, paraffin hydrocarbons, polyethylene glycols or higheralkanols. It is also possible to use gelatin rectal capsules thatcontain a combination of the active ingredient and a base substance;suitable base substances are, for example, liquid triglycerides,polyethylene glycols or paraffin hydrocarbons.

There are suitable for parenteral administration especially aqueoussolutions of an active ingredient in water-soluble form, for example awater-soluble salt, also suspensions of the active ingredient, such ascorresponding oily injection suspensions, there being used suitablelipophilic solvents or vehicles, such as fatty oils, for example sesameoil, or synthetic fatty acid esters, for example ethyl oleate ortriglycerides, or aqueous injection suspensions that contain substancesthat increase viscosity, for example sodium carboxymethylcellulose,sorbitol and/or dextran and optionally also stabilisers.

The following Examples illustrate the invention described above; theyare not, however, intended to limit in any way the scope thereof.Temperatures are given in Centgrade; pressures are indicated in mbar.

EXAMPLE 1

180 g of N,N'-bis-(diphenylmethylene)-1,2-propylenediamine are dissolvedin 540 ml of acetic acid. 3 g of platinum oxide are added and themixture is scavenged thoroughly with argon and then hydrogen isintroduced while stirring vigorously until starting material can nolonger be detected by thin layer chromatography (silica gel 60, diethylether: R_(f) =0.62) (generally 24 to 48 hours). The reaction solution isdiluted with 150 ml of ethanol, the catalyst is filtered off and thenthe filtrate is concentrated to dryness by evaporation under reducedpressure in a water bath. The oil residue obtained after concentrationby evaporation is triturated with 375 ml of 10% sodium hydroxidesolution and extracted twice with 375 ml of diethyl ether each time. Theether phases are combined, washed twice with 70 ml of saturated sodiumchloride solution each time, dried over magnesium sulphate and thenevaporated to dryness on a water bath, first at approximately 20 mbarand then at approximately 0.03 mbar. The residue is dissolved inapproximately 300 ml of ethanol, water is added until the solutionstarts to become cloudy (approximately 20 ml) and then the whole iscaused to crystallise in an ice bath. The precipitated crystals arefiltered with suction, washed with a little methanol and driedthoroughly at approximately 0.03 mbar.N,N'-bis-(diphenylmethyl)-1,2-propylenediamine having a melting point of72°-75° C. is obtained which can be further purified byrecrystallisation from approximately double the quantity of methanol andby precipitation with water, and then melts at 75°-77° C.

The starting material can be manufactured, for example, as follows:

255.1 g of benzophenone, 298 ml of 1,2-diaminopropane and 0.2 g ofp-toluenesulphonic acid are mixed and heated for 30 minutes underreflux. Approximately 250 ml are then distilled off, the remainder isallowed to cool to approximately 80° C. and approximately 350 ml of2-ethoxyethanol (ethylene glycol monoethyl ether) are added, followed,while stirring, by 70 ml of water and the whole is allowed tocrystallise in an ice bath.N,N'-bis-(diphenylmethylene)-1,2-propylenediamine is obtained which canbe purified by recrystallisation from ethanol (approximately 180 ml) andshould be dried thoroughly before further reaction.

In an analogous manner, there are obtained, starting from benzophenone,by reaction with m-xylylenediamine viaN,N'-bis-(diphenylmethylene)-m-xylylenediamine,N,N'-bis-(diphenylmethyl)-m-xylylenediamine, m.p. 89°-90° C. (fromisopropanol), by reaction with 1,3-propylenediamine viaN,N'-bis-(diphenylmethylene)-1,3-propylenediamine,N,N'-bis-(diphenylmethyl)-1,3-propylenediamine, m.p. 83°-84° C. (fromacetone), and by reaction with p-xylylenediamine viaN,N'-bis-(diphenylmethylene)-p-xylylenediamine,N,N'-bis-(diphenylmethyl)-p-xylylenediamine, m.p. 92°-94° C. (fromdiethyl ether).

EXAMPLE 2

20.2 g of triethylamine, 7.4 g of N-methyl-ethylenediamine and 25.2 g ofbenzyl chloride are added in succession, while stirring, to 240 ml ofacetonitrile; the mixture is boiled under reflux for approximately 48hours and the precipitated triethylammonium chloride is filtered off.The filtrate is concentrated by evaporation under reduced pressure. Theoily residue is taken up in 100 ml of diethyl ether and extracted byshaking with 50 ml of 10% sodium hydroxide solution. The aqueous phaseis washed with 100 ml of ether. The ether phases are combined, washedtwice with 50 ml of saturated sodium chloride solution each time, driedover magnesium sulphate and concentrated to dryness by evaporation undermild conditions. The residue obtained after concentration by evaporationis distilled under reduced pressure (under 0.1 mbar).N,N'-dibenzyl-N-methyl-ethylenediamine is obtained having a b.p.₀.028=123° C.

In an analogous manner it is also possible to obtain: by reaction ofethylenediamine with o-methylbenzyl chloride,N,N'-di-(o-methylbenzyl)-ethylenediamine, m.p. 38°-39° C., and byreaction of 1,2- or 1,3-propylenediamine or m- or p-xylylenediamine withbenzhydryl chloride, N,N'-bis-(diphenylmethyl)-1,2-propylenediamine,m.p. 75°-77° C. (from methanol/water),N,N'-bis-(diphenylmethyl)-1,3-propylenediamine, m.p. 83°-84° C. (fromacetone), N,N'-bis-(diphenylmethyl)-m-xylylenediamine, m.p. 89°-90° C.(from isopropanol) and N,N'-bis-(diphenylmethyl)-p-xylylenediamine, m.p.92°-94° C. (from diethyl ether), respectively.

EXAMPLE 3

5.3 g of N,N'-di-(o-methylbenzylidene)-ethylenediamine, dissolved in 75ml of tetrahydrofuran, are added dropwise to a suspension of 2.0 g oflithium aluminium hydride in 30 ml of tetrahydrofuran. The mixture isheated under reflux for 30 minutes, the excess of reducing agent isdecomposed with water while cooling with ice, the whole is poured into200 ml of sodium hydroxide solution (10% by weight) and extracted 3times by shaking with 150 ml of diethyl ether each time. From thecombined diethyl ether extracts the hydrochloride is precipitated, inform of a white powder, by adding a solution of hydrogen chloride indiethyl ether. The hydrochloride is separated by filtration, shaken with150 ml of diethyl ether and 150 ml of 10% sodium hydroxide solution. Theether phase is dried over magnesium sulphate and concentrated to drynessby evaporation. The residue is recrystallised from ethyl acetate.N,N'-di-(o-methylbenzyl)-ethylenediamine having a meltinp point of38°-39° C. is obtained.

The starting material can be manufactured, for example, as follows:

A mixture of 24 g of 2-methylbenzaldehyde, 200 ml of toluene and 5.8 gof ethylenediamine is stirred overnight. Approximately 125 ml are thendistilled off under reduced pressure. The precipitatedN,N'-di-(o-methylbenzylidene)-ethylenediamine is filtered with suction.It melts at 51°-52° C.

EXAMPLE 4

6.15 g of N,N'-dibenzyl-N-methyl-ethylenediamine are dissolved in 60 mlof diethyl ether. Hydrogen chloride is then introduced while stirringand cooling (if necessary in an acetone/dry-ice bath) until a sample,dried on a clay plate, melts at 227°-229° C. The precipitated product isfiltered with suction, washed with ether and dried to constant weightunder reduced pressure (under 0.1 mbar).N,N'-dibenzyl-N-methyl-ethylenediamine dihydrochloride is obtained, m.p.227°-229° C.

EXAMPLE 5

A solution of 9.2 g of α-chlorophenylacetic acid methyl ester, dissolvedin 10 ml of acetonitrile, is added dropwise in the course of 10 minutes,while stirring, to a mixture of 11.3 g ofN-diphenylmethyl-ethylenediamine, 5.05 g of triethylamine and 70 ml ofacetonitrile. The mixture is then heated under reflux for 18 hours. Itis then concentrated to dryness by evaporation under reduced pressure,triturated with 100 ml of 10% sodium hydroxide solution and extractedtwice by shaking with 100 ml of diethyl ether each time. The etherphases are combined, washed three times with 30 ml of saturated sodiumchloride solution each time, dried over magnesium sulphate andconcentrated by evaporation. The residue obtained after concentration byevaporation is shaken with 10% (by weight) sodium hydroxide solution anddiethyl ether in order to remove any excess triethylamine. The etherphases are further treated as indicated above. Finally, drying iseffected at approximately 0.15 mbar.N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine isobtained which is converted into the diacetate for characterisation. Forthat purpose, 14.8 g of base are dissolved in 15 ml of diethyl ether and15 ml of hexane, and glacial acetic acid is added dropwise whilestirring and cooling. The precipitate is filtered with suction,recrystallised from approximately 360 ml of diethyl ether and 90 ml ofhexane and dried under reduced pressure (under 0.2 mbar). TheN-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine acetatemelts at 78°-81° C. PureN-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediamine can befreed from this by treatment with 10% sodium hydroxide solution,extraction by shaking with diethyl ether, drying over magnesium sulphateand evaporating off the solvent.

The N-diphenylmethyl-ethylenediamine used as starting material can bemanufactured, for example, as follows:

A mixture of 90.15 g of ethylenediamine, 50.7 g of benzhydryl chlorideand 300 ml of acetonitrile is heated under reflux for 24 hours. It ispartitioned between 400 ml of diethyl ether and 175 ml of 10% sodiumhydroxide solution, the ether phase is separated off, dried overmagnesium sulphate, evaporated to dryness and distilled under reducedpressure. N-diphenylmethylethylenediamine is obtained, b.p.₀.13=116°-124° C., m.p. 23°-24° C.

The α-chlorophenylacetic acid methyl ester used as the starting materialcan be manufactured, for example, as follows:

16 g of methanol are added dropwise while stirring to 94.5 g ofα-chlorophenylacetyl chloride. 5 drops of concentrated sulphuric acidare added, the mixture is boiled for 2 hours while stirring, allowed tocool and poured onto 150 ml of ice water. The organic phase is separatedoff and the aqueous phase is extracted twice by shaking with 50 ml ofdiethyl ether each time. The organic phases are combined, neutralisedwith 50 ml of saturated potassium carbonate solution, washed with 50 mlof water, dried over sodium sulphate and concentrated by evaporationunder reduced pressure. The residue obtained after concentration byevaporation is distilled under reduced pressure (under 0.2 mbar). Theα-chlorophenylacetic acid methyl ester boils under 0.13 mbar at 62° C.;(n_(D) ²⁰ : 1.5268).

In an analogous manner, there can be obtained by reaction ofN-diphenylmethylethylenediamine with benzyl chloride or 1-phenylethylchloride, N,N-dibenzyl-N'-diphenylmethylethylenediamine, m.p. 89°-91° C.(from diisopropyl ether), andN-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine, m.p. of thedihydrochloride 160° C. (with decomposition), respectively.

EXAMPLE 6

85 ml of 10% sodium hydroxide solution are added to 8.5 g ofN-(α-methoxycarbonylbenzyl)-N'-diphenylmethylethylenediamine diacetateand the mixture is extracted three times by shaking with 85 ml ofdiethyl ether each time. The ether solutions of theN-(α-methoxycarbonylbenzyl)-N'-diphenylmethylethylenediamine arecombined and dried over magnesium sulphate. Hydrogen chloride is thenintroduced while cooling well (if necessary in an acetone/dry-ice bath)until the base has completely precipitated as the dihydrochloride. Thesalt is filtered with suction, washed several times with ether and driedto constant weight under reduced pressure (under 0.1 mbar).N-(α-methoxycarbonylbenzyl)-N'-diphenylmethyl-ethylenediaminedihydrochloride having a melting point of 148° C. (with decomposition)is obtained.

EXAMPLE 7

A mixture of 18.3 g of benzhydrylamine, 10 g of triethylamine and 60 mlof acetonitrile is added dropwise to a boiling mixture of 13.2 g of1,4-bis-(bromomethyl)-benzene in 60 ml of acetonitrile. The mixture isleft to boil overnight, is greatly concentrated, and partitioned between200 ml of ether and 200 ml of 10% sodium hydroxide solution,concentrated by evaporation and recrystallised from diethyl ether.N,N'-bis-(diphenylmethyl)-p-xylylenediamine having a melting point of92°-94° C. is obtained.

In an analogous manner thare are obtained by reaction ofo-methylbenzylamine with 1,2-dibromoethane,N,N'-di-(o-methylbenzyl)-ethylenediamine, m.p. 38°-39° C. (from ethylacetate), and by reaction of benzhydrylamine with 1,2- or1,3-dibromopropane or 1,3-bis-(bromomethyl)-benzene,N,N'-bis-(diphenylmethyl)-1,2-propylenediamine, m.p. 75°-77° C. (frommethanol/water), N,N'-bis-(diphenylmethyl)-1,3-propylenediamine, m.p.83°-84° C. (from acetone) andN,N'-bis-(diphenylmethyl)-m-xylylenediamine, m.p. 89°-90° C. (fromisopropanol), respectively.

EXAMPLE 8

11 g of N-diphenylmethyl-ethylenediamine, 10.1 g of triethylamine and7.0 g of 1-phenylethyl chloride are dissolved, while stirring, in 85 mlof acetonitrile and heated under reflux for 30 hours. The solution isconcentrated by evaporation under reduced pressure, 50 ml of 10% sodiumhydroxide solution are added and the mixture is extracted thoroughly byshaking with diethyl ether. The ether extracts are combined, dried oversodium sulphate and concentrated by evaporation.N-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine is obtained in theform of a yellow oil which can be purified chromatographically oversilica gel with methanol/ethyl acetate (1:1) as the eluant and, forcharacterisation, can be converted into the dihydrochloride, having amelting point of 160° C., as described in Example 4.

EXAMPLE 9

A solution of 2.9 g of benzyl chloride in 25 ml of acetonitrile is addedto 5.6 g of N-diphenylmethyl-ethylenediamine in 30 ml of boilingacetonitrile. The mixture is heated under reflux for 12 hours,concentrated and partitioned between diethyl ether and 10% sodiumhydroxide solution. The organic phases are dried over sodium sulphateand concentrated by evaporation. The residue can be recrystallised frommethanol or diisopropyl ether.N,N-dibenzyl-N'-diphenylmethyl-ethylenediamine having a melting point of89°-91° C. is obtained.

EXAMPLE 10

25 g of N,N'-bis-(diphenylmethyl)-1,2-propylenediamine dissolved in 75ml of methanol are added dropwise while stirring vigorously at 10° C. toa solution of 12.05 g of methanesulphonic acid in 175 ml of water. Themixture is stirred for a further 15 minutes at room temperature,inoculated and left to crystallise overnight. The methanol is then drawnoff under reduced pressure and the remainder is left to crystallisecompletely at 0° C., is filtered with suction, washed with 40 ml of icewater and left to dry under 0.1 to 0.4 mbar, first for a few hours atroom temperature and then overnight at 50° C.N,N'-bis-(diphenylmethyl)-1,2-propylenediamine bis-methanesulphonatehaving a melting point of 218°-219° C. (with decomposition) is obtained.

EXAMPLE 11

Tablets containing 5 mg ofN,N'-bis-(diphenylmethyl)-1,2-propylenediamine bis-methanesulphonate canbe obtained, for example, as follows:

    ______________________________________                                        Composition: (for 10,000 tablets):                                            ______________________________________                                        active ingredient 50 g                                                        lactose           460 g                                                       maize starch      450 g                                                       polyvinylpyrrolidone                                                                            20 g                                                        magnesium stearate                                                                              10 g                                                        colloidal silica  10 g                                                        water             q.s.                                                        ______________________________________                                    

The active ingredient, the lactose and 400 g of the maize starch aremixed and moistened with an aqueous solution of polyvinylpyrrolidone.The mixture is granulated and dried and the magnesium stearate, thecolloidal silica and the maize starch left over are added. The mixtureis forced through a sieve, mixed and pressed to form tablets weighing100 mg (diameter: 6 mm).

EXAMPLE 12

Tablets containing 20 mg ofN,N'-bis-(diphenylmethyl-1,2-propylenediamine bis-methanesulphonate(active ingredient) can be manufactured, for example, in the followingcomposition:

    ______________________________________                                        Composition: (for 10,000 tablets):                                            ______________________________________                                        active ingredient 200 g                                                       lactose           500 g                                                       wheat starch      773 g                                                       colloidal silica   13 g                                                       talc               12 g                                                       magnesium stearate                                                                               2 g                                                        ______________________________________                                    

Manufacture

The active ingredient is mixed with lactose, part of the wheat starchand with the colloidal silica and the mixture is forced through a sieve.A further part of the wheat starch is made into a paste with 5 times thequantity of water on a water bath and the powder mixture is kneaded withthis paste until a slightly plastic substance has been formed. Thissubstance is forced through a sieve having a mesh width of approximately1 mm, dried and the dry granulate is again forced through a sieve. Theremaining wheat starch, the talc and the magnesium stearate are thenadmixed. The resulting tablet mixture is pressed to form tablets eachweighing 150 mg and having a breaking notch.

EXAMPLE 13

Tablets containing 10 mg ofN,N'-bis-(diphenylmethyl)-1,2-propylenediamine bis-methanesulphonate(active ingredient) can be manufactured, for example, in the followingcomposition:

    ______________________________________                                        Composition: (for 10,000 tablets):                                            ______________________________________                                        active ingredient 100 g                                                       wheat starch      295 g                                                       lactose           500 g                                                       colloidal silica   50 g                                                       talc               50 g                                                       magnesium stearate                                                                               5 g                                                        ______________________________________                                    

Manufacture

The active ingredient is mixed with part of the wheat starch, with thelactose and the colloidal silica and the mixture is forced through asieve. A further part of the wheat starch is made into a paste with 5times the quantity of water on a water bath and the powder mixture iskneaded with this paste until a slightly plastic substance has beenformed.

The plastic substance is pressed through a sieve having a mesh width ofapproximately 3 mm, dried and the dry granulate is again forced througha sieve. The remaining wheat starch, the talc and the magnesium stearateare admixed and the resulting mixture is pressed to form tabletsweighing 100 mg (with a breaking notch).

EXAMPLE 14

Capsules having a content of 10 mg ofN,N'-bis-(diphenylmethyl)-1,2-propylenediamine bis-methanesulphonate(active ingredient) are manufactured, for example, as follows:

    ______________________________________                                        Ingredients: (for 10,000 capsules):                                           ______________________________________                                        active ingredient 100 g                                                       lactose           360 g                                                       magnesium stearate                                                                               40 g                                                       ______________________________________                                    

The ingredients are mixed in a suitable mixer, forced through a No. 40sieve and mixed again. Each 0.05 g of the mixture is introduced into agelatin capsule No. 3.

EXAMPLE 15

In a manner analogous to that described in Examples 11 to 14, it is alsopossible to manufacture pharmaceutical preparations containing one ofthe compounds of the formula I mentioned in Examples 1 to 9 or in thedescription.

I claim:
 1. A method of easing the breathing activity of a warm-bloodedorganism suffering from respiratory disorders or being exposed tounfavourable respiratory conditions, comprising administering to theorganism a breathing effectively easing amount of a compound of theformula

    R.sub.1 --CH(R.sub.2)--N(R.sub.3)--R.sub.4                 (IC)

in which R₃ is hydrogen, methyl or benzyl, and R₄ is: the group --alk₁--X--alk₂ --R₅, or R₃ and R₄ together are the group --alk₃ --NH--alk₄wherein: alk₁ and alk₂ are the same or different and are each loweralkylidene, alk₃ and alk₄ are the same or different and are eachethylene X is a direct bond, methylene or phenylene, R₅ is: hydroxy,amino, or the group

    --N(R.sub.6)--CH(R.sub.7)--R.sub.8 ;

each of R₁ and R₈ being the same or a different one of the groups:phenyl or phenyl substituted by one of the substituents: methyl andhalogen having an atomic number of at most 35, any such halogensubstituent being in positions meta- or para- of the phenyl nucleus, R₆is hydrogen or lower alkyl, but at least one of R₃ and R₆ must behydrogen; R₂ and R₇ are the same or different and are each one of thefollowing: hydrogen, lower alkyl, phenyl, phenyl substituted as definedfor R₁, lower alkoxy-carbonyl of from 2 to 5 carbon atoms; and groupsdefined as "lower alkyl" hereinbefore having at most 7 carbon atoms; orof a pharmaceutically acceptable salt of the compound of Formula IC. 2.The method of claim 1, wherein said compound of Formula IC isN,N'-bis-(diphenylmethyl)-1,3-propylenediamine.
 3. The method of claim1, wherein said compound of Formula IC isN,N'-bis-(diphenylmethyl)-p-xylylenediamine.
 4. The method of claim 1,wherein said compound of Formula IC isN-diphenylmethyl-N'-(1-phenylethyl)-ethylenediamine.
 5. The method ofclaim 1, wherein said compound of Formula IC isN-diphenylmethyl-N'-(α-methoxycarbonylbenzyl)-ethylenediamine.
 6. Themethod of claim 1, wherein said compound of Formula IC isN,N'-bis-(diphenylmethyl)-m-xylylenediamine.
 7. The method of claim 1,wherein said compound of Formula IC isN,N-dibenzyl-N'-diphenylmethyl-ethylenediamine.
 8. The method of claim1, wherein said compound of Formula IC isN,N'-di-(o-methylbenzyl)-ethylenediamine.
 9. The method of claim 1,wherein said compound of Formula IC isN,N'-dibenzyl-N-methyl-ethylenediamine.
 10. The method of claim 1,wherein said compound of Formula IC isN,N'-bis-(diphenylmethyl)-ethylenediamine.
 11. The method of claim 1,wherein said compound of Formula IC is N-diphenylmethyl-ethylenediamine.12. The method of claim 1, wherein said compound of Formula IC isN,N'-di-(p-methylbenzyl)-ethylenediamine.
 13. The method of claim 1,wherein 1-diphenylmethyl-piperazine or a pharmaceutically acceptablesalt thereof is used as the active ingredient.
 14. The method of claim1, wherein 2-diphenylmethylamino-ethanol or a pharmaceuticallyacceptable salt thereof, is used as the active ingredient.
 15. Themethod of claim 1, wherein N,N'-dibenzylethylenediamine or apharmaceutically acceptable salt thereof is used as the activeingredient.
 16. The method of claim 1, wherein 1-benzyl-piperazine or apharmaceutically acceptable salt thereof is used as the activeingredient.
 17. The method of claim 1, whereinN,N'-di-(p-chlorobenzyl)-ethylendiamine or a pharmaceutically acceptablesalt thereof is used as the active ingredient.
 18. The method of claim1, wherein N,N'-di-(3,4-dichlorobenzyl)-ethylenediamine or apharmaceutically acceptable salt thereof is used as the activeingredient.
 19. The method of claim 1, whereinN,N'-di-(1-phenylethyl)-ethylenediamine or a pharmaceutically acceptablesalt thereof is used as the active ingredient.
 20. The method of claim1, wherein N,N'-bis-(diphenylmethyl)-1,2-propylenediamine or apharmaceutically acceptable salt thereof is used as the activeingredient.
 21. A method according to claim 1, wherein a pharmaceuticalpreparation according to either one of claims 16 and 17 is administered.